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Microsoft 365: A guide to the updates
Microsoft 365 (and Office 365) subscribers get more frequent software updates than those who have purchased Office without a subscription, which means subscribers have access to the latest features, security patches, and bug fixes. But it can be hard to keep track of the changes in each update and know when they’re available. We’re doing this for you, so you don’t have to.
Following are summaries of the updates to Microsoft 365/Office 365 for Windows over the past year, with the latest releases shown first. We’ll add info about new updates as they’re rolled out.
Note: This story covers updates released to the Current Channel for Microsoft 365/Office 365 subscriptions. If you’re a member of Microsoft’s Office Insider preview program or want to get a sneak peek at upcoming features, see the Microsoft 365 Insider blog.
Version 2605 (Build 20026.20168)Release date: June 9, 2026
This build offers “various fixes to functionality and performance,” according to Microsoft.
Get more info about Version 2605 (Build 20026.20168).
Version 2605 (Build 20026.20140)Release date: June 3, 2026
This build fixes a single bug, in which images didn’t display when using top and bottom text wrapping in classic Outlook.
Get more info about Version 2605 (Build 20026.20140).
Version 2605 (Build 20026.20112)Release date: May 26, 2026
This build offers “various fixes to functionality and performance,” according to Microsoft.
Get more info about Version 2605 (Build 20026.20112).
Version 2605 (Build 20026.20076)Release date: May 20, 2026
This build fixes several bugs, including one in which Excel or PowerPoint closed unexpectedly in rare cases while the user was actively co-authoring, particularly when opening a document for the first time.
Get more info about Version 2605 (Build 20026.20076).
Version 2604 (Build 19929.20172)Release date: May 14, 2026
This build fixes a bug in Outlook in which sending mail failed when multiple Exchange accounts were configured.
Get more info about Version 2604 (Build 19929.20172).
Version 2604 (Build 19929.20164)Release date: May 12, 2026
The build plugs a number of security holes. For details, see Release notes for Microsoft Office security updates.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2604 (Build 19929.20164).
Version 2604 (Build 19929.20136)Release date: May 5, 2026
This build fixes a bug in which Outlook closed unexpectedly after replying to a mail item with labels.
Get more info about Version 2604 (Build 19929.20136).
Version 2604 (Build 19929.20106)Release date: April 29, 2026
This build includes “various fixes to functionality and performance,” according to Microsoft.
Get more info about Version 2604 (Build 19929.20106).
Version 2604 (Build 19929.20090)Release date: April 21, 2026
This build includes “various fixes to functionality and performance,” according to Microsoft.
Get more info about Version 2604 (Build 19929.20090).
Version 2603 (Build 19822.20182)Release date: April 14, 2026
In this build, Copilot can now edit your PowerPoint documents. Copilot can start a new presentation or build on an existing one, generate slides, update content, improve layouts, and polish design, while preserving formatting, structure, and branding.
The build also plugs a number of security holes. For details, see Release notes for Microsoft Office security updates.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2603 (Build 19822.20182).
Version 2603 (Build 19822.20168)Release date: April 9, 2026
This build fixes several bugs, including one in Outlook in which users could not close the Copilot chat pane using a keyboard. Users can now close the pane by navigating to the Close button using a keyboard or by using the assigned keyboard shortcut.
Get more info about Version 2603 (Build 19822.20168).
Version 2603 (Build 19822.20142)Release date: March 31, 2026
This build includes “various fixes to functionality and performance,” according to Microsoft.
Get more info about Version 2603 (Build 19822.20142).
Version 2603 (Build 19822.20114)Release date: March 24, 2026
This build fixes a single bug in which PowerPoint sometimes closed unexpectedly when opening a newly created empty file from the OneDrive folder.
Get more info about Version 2603 (Build 19822.20114).
Version 2602 (Build 19725.20190)Release date: March 18, 2026
This build fixes an Outlook bug in which updating a single instance of a recurring meeting in a Microsoft 365 group calendar updated the entire series.
Get more info about Version 2602 (Build 19725.20190).
Version 2602 (Build 19725.20172)Release date: March 10, 2026
This build introduces agent mode in Word, which adds a conversational chat experience that helps create, edit, and refine document content as you work. In addition, the build fixes a bug that impacted the rendering of extended characters in calendar items, causing certain characters to appear as question marks.
The build also plugs a number of security holes. For details, see Release notes for Microsoft Office security updates.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2602 (Build 19725.20172).
Version 2602 (Build 19725.20152)Release date: March 3, 2026
This build fixes a bug in which closing a document sometimes remained in progress indefinitely after the Office app resumed from sleep or hibernation.
Get more info about Version 2602 (Build 19725.20152).
Version 2602 (Build 19725.20126)Release date: February 24, 2025
This build fixes several bugs, including one that caused OneNote to close unexpectedly upon startup.
Get more info about Version 2602 (Build 19725.20126).
Version 2601 (Build 19628.20214)Release date: February 17, 2025
This build includes, in Microsoft’s words, “various fixes to functionality and performance.”
Get more info about Version 2601 (Build 19628.20214).
Version 2601 (Build 19628.20204)Release date: February 10, 2026
This build fixes a bug that sometimes prevented users from opening emails with the Encrypt Only label in Outlook.
It also plugs a number of security holes. For details, see Release notes for Microsoft Office security updates.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2601 (Build 19628.20204).
Version 2601 (Build 19628.20166)Release date: February 3, 2026
This build includes, in Microsoft’s words, “various fixes to functionality and performance.”
Get more info about Version 2601 (Build 19628.20166).
Version 2601 (Build 19628.20150)Release date: January 27, 2025
In this build, OneNote applies your chosen proofing language more consistently, so you don’t have to reset it for every paragraph when writing in multiple languages. In addition, the build fixes several bugs, including one that caused Office applications to become unresponsive when profile card-related activities were performed.
Get more info about Version 2601 (Build 19628.20150).
Version 2512 (Build 19530.20184)Release date: January 21, 2025
This build includes, in Microsoft’s words, “Various fixes to functionality and performance.”
Get more info about Version 2512 (Build 19530.20184).
Version 2512 (Build 19530.20144)Release date: January 13, 2026
This build fixes a number of bugs, including one that caused Excel, PowerPoint, and Word to become unresponsive when profile card-related activities were performed.
It also plugs a number of security holes. For details, see Release notes for Microsoft Office security updates.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2512 (Build 19530.20144).
Version 2512 (Build 19530.20138)Release date: January 8, 2025
This build offers, in Microsoft’s words, “Various fixes to functionality and performance.”
Get more info about Version 2512 (Build 19530.20138).
Version 2511 (Build 19426.20218)Release date: December 16, 2025
This build offers, in Microsoft’s words, “Various fixes to functionality and performance.”
Get more info about Version 2511 (Build 19426.20218).
Version 2511 (Build 19426.20186)Release date: December 9, 2025
This Patch Tuesday build offers, in Microsoft’s words, “Various fixes to functionality and performance.” The build also has a variety of security updates (see details).
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2511 (Build 19426.20186).
Version 2511 (Build 19426.20170)Release date: December 3, 2025
This build includes, in Microsoft’s words, “Various fixes to functionality and performance.”
Get more info about Version 2511 (Build 19426.20170).
Version 2510 (Build 19328.20244)Release date: November 20, 2025
This build fixes a bug in Outlook that caused users to see “Contacting the server for information” repeatedly when loading some emails.
Get more info about Version 2510 (Build 19328.20244).
Version 2510 (Build 19328.20232)Release date: November 18, 2025
This build includes, in the words of Microsoft, “various fixes to functionality and performance.”
Get more info about Version 2510 (Build 19328.20232).
Version 2510 (Build 19328.20190)Release date: November 11, 2025
This Patch Tuesday build fixes a bug in Outlook that caused some recipients to be unable to access OneDrive links shared with them via email. The build also has a variety of security updates (see details).
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2510 (Build 19328.20190).
Version 2510 (Build 19328.20178)Release date: November 4, 2025
This build fixes a single bug, in which @mention searches produced no results in Office apps.
Get more info about Version 2510 (Build 19328.20178).
Version 2510 (Build 19328.20158)Release date: October 30, 2025
This build introduces a new Get Data dialog in Windows that simplifies finding and using external data, and adds Analyze Data to the Data tab.
The build also fixed an bug in Outlook that prevented users from downloading web add-ins in some virtualized environments.
Get more info about Version 2510 (Build 19328.20158).
Version 2509 (Build 19231.20216)Release date: October 21, 2025
This build has, in Microsoft’s words, “various fixes to functionality and performance.”
Get more info about Version 2509 (Build 19231.20216).
Version 2509 (Build 19231.20194)Release date: October 14, 2025
This build has a variety of security updates (see details), along with various fixes to functionality and performance.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2509 (Build 19231.20194).
Version 2509 (Build 19231.20172)Release date: October 7, 2025
This build has, in Microsoft’s words, “various fixes to functionality and performance.”
Get more info about Version 2509 (Build 19231.20172).
Version 2509 (Build 19231.20156)Release date: October 1, 2025
This build fixes two bugs, one in Excel in which ribbon controls were not rendered when rejoining Office sessions in a virtual machine, Azure Virtual Desktop, or remote desktop environment, and another that caused Outlook to terminate unexpectedly when starting.
Get more info about Version 2509 (Build 19231.20156).
Version 2508 (Build 19127.20264)Release date: September 23, 2025
This build has, in Microsoft’s words, “various fixes to functionality and performance.”
Get more info about Version 2508 (Build 19127.20264).
Version 2508 (Build 19127.20240)Release date: September 16, 2025
This build has, in Microsoft’s words, “various fixes to functionality and performance.”
Get more info about Version 2508 (Build 19127.20240).
Version 2508 (Build 19127.20222)Release date: September 9, 2025
This build has multiple security updates (see details), along with various fixes to functionality and performance.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2508 (Build 19127.20222).
Version 2508 (Build 19127.20192)Release date: September 3, 2025
This build fixes a bug in which some Outlook add-ins were getting “Office.auth.getAccessToken is not a function” errors.
Get more info about Version 2508 (Build 19127.20192).
Version 2508 (Build 19127.20154)Release date: August 26, 2025
This build fixes a bug that caused Outlook to terminate unexpectedly when sending a meeting invite with an encryption label. It also adds support for pixelated rendering of embedded images in SVG assets for the entire Office suite.
Get more info about Version 2508 (Build 19127.20154).
Version 2507 (Build 19029.20208)Release date: August 19, 2025
This build fixes a variety of bugs.
Get more info about Version 2507 (Build 19029.20208).
Version 2507 (Build 19029.20184)Release date: August 12, 2025
This build fixes a bug which required users to restart Outlook to open a .msg file after initially accessing it once. The build also includes a variety of security updates (see details).
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2507 (Build 19029.20184).
Version 2507 (Build 19029.20156)Release date: August 5, 2025
This build fixes a single bug, in which users had to restart Outlook to open a .msg file after initially accessing it once.
Get more info about Version 2507 (Build 19029.20156).
Version 2507 (Build 19029.20136)Release date: July 30, 2025
This build fixes a wide variety of bugs, including in which Outlook closed unexpectedly shortly after launch, and another in Word in which the word count sometimes displayed incorrectly.
Get more info about Version 2507 (Build 19029.20136).
Version 2506 (Build 18925.20184)Release date: July 22, 2025
This build fixes two bugs, one that caused the Copilot Command Center to continue to be visible after disabling the Copilot user interface, and another in which when creating handouts in PowerPoint, certain characters (full-width numbers) couldn’t be properly transferred to the handout.
Get more info about Version 2506 (Build 18925.20184).
Version 2506 (Build 18925.20168)Release date: July 15, 2025
This build fixes two bugs, one that caused Visio 32-bit to close unexpectedly when using the Drawing control, particularly in setups involving COM components or .NET integrations, and another in Word in which copying and pasting content between documents sometimes changed the applied style unexpectedly.
Get more info about Version 2506 (Build 18925.20168).
Version 2506 (Build 18925.20158)Release date: July 8, 2025
This Patch Tuesday build fixes several bugs in Outlook, PowerPoint, Word, and the whole Office suite, including one that caused the Copilot icon to unexpectedly display in Outlook when Copilot had been disabled by the admin in government cloud.
The release also includes a variety of security updates (see details).
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2506 (Build 18925.20158).
Version 2506 (Build 18827.20176)Release date: July 1, 2025
This build fixes a wide variety of bugs, including one in Word in which print preview sometimes stopped working when printing long emails.
Get more info about Version 2506 (Build 18827.20176).
Version 2505 (Build 18827.20176)Release date: June 26, 2025
This build introduces several new features, including one in Excel in which the PivotTables dialog box interface has been replaced by a redesigned panel, making it easier to view all of your options and simpler to change your data selection before inserting a recommended PivotTable.
Get more info about Version 2505 (Build 18827.20176).
Version 2505 (Build 18827.20164)Release date: June 17, 2025
This build fixes a bug that caused the “Try the new Outlook” toggle to be enabled when working in Classic Outlook side by side with the new Outlook.
Get more info about Version 2505 (Build 18827.20164).
Version 2505 (Build 18827.20150)Release date: June 10, 2025
This build fixes several bugs, including one for the entire Office suite in which a Save As attempt on an existing file didn’t complete successfully, and subsequent attempts continued to encounter issues when trying to save to a file that no longer existed.
This Patch Tuesday release also includes a variety of security updates: see details.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2505 (Build 18827.20150).
Version 2505 (Build 18827.20140)Release date: June 3, 2025
This build offers a variety of bug and performance fixes.
Read about Version 2505 (Build 18827.20140).
Version 2504 (Build 18730.20186)Release date: May 20, 2025
This build introduces a new PowerPoint feature: Notification emails for mentions, tasks, comments, and replies will now contain context previews even when the source document is encrypted, and the email will inherit the document’s security policies.
Get more info about Version 2504 (Build 18730.20186).
Version 2504 (Build 18730.20168)Release date: May 13, 2025
This build fixes a bug in which users were seeing high CPU usage when typing in Outlook. It also includes a variety of security updates: see details.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2504 (Build 18730.20168).
Version 2504 (Build 18730.20142)Release date: May 6, 2025
This build includes various bug and performance fixes.
Get more info about Version 2504 (Build 18730.20142).
Version 2504 (Build 18730.20122)Release date: April 29, 2025
This build fixes a wide variety of bugs, including one in which PowerPoint was unable to open a file from a network mapped drive from File Explore, another in which Word closed unexpectedly when opening .doc files, and another for the entire Office suite in which large 3D files couldn’t be inserted.
Get more info about Version 2504 (Build 18730.20122).
Version 2503 (Build 18623.20208)Release date: April 17, 2025
This build fixes a bug that could cause Excel to stop responding.
Get more info about Version 2503 (Build 18623.20208).
Version 2503 (Build 18623.20178)Release date: April 8, 2025
This build fixes a single bug in Word in which users may have encountered an issue with saving, seeing the message “saving…” in the title bar. It also includes a variety of security updates. Go here for details.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2503 (Build 18623.20178).
Version 2503 (Build 18623.20156)Release date: April 2, 2025
This build lets you use Dark Mode in Excel, which darkens your entire sheet, including cells, and may reduce eye strain. It also fixes several bugs, including one in Word in which opening specific files that contain many tracked changes and comments resulted in poor performance, and one in PowerPoint in which the app was not displaying the icon for an inserted PDF object.
Get more info about Version 2503 (Build 18623.20156).
Version 2502 (Build 18526.20168)Release date: March 11, 2025
This build fixes several bugs, including one in which some Word files with numerous tracked changes and comments were slow. It also includes a variety of security updates: see details.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2502 (Build 18526.20168).
Version 2502 (Build 18526.20144)Release date: March 5, 2025
This build fixes a wide variety of bugs, including one in Word in which the default font size may not be 12pt as expected, and another in which PowerPoint automatically closed when the system went into hibernate or sleep mode.
Get more info about Version 2502 (Build 18526.20144).
Version 2501 (Build 18429.20158)Release date: February 11, 2025
This build removes the option to display Track Changes balloons in left margin in Word. It also includes a variety of security updates. See “Release notes for Microsoft Office security updates” for details.
What IT needs to know: Because this is a security update, it should be applied relatively soon. Over the next few weeks, check for reports about problematic issues, and if all seems well, apply the update.
Get more info about Version 2501 (Build 18429.20158).
Eclipse IDE 2026-06 aneb Eclipse 4.40
The hidden cost of enterprise AI: 6.4 hours a week babysitting bots
While AI is proliferating across the workplace, it is introducing a new productivity paradox: While the technology makes work feel faster, it actually pushes more burden onto employees to provide context, perform quality checks, then rinse and repeat across numerous disparate tools.
This, according to a new survey of 6,000 full-time digital workers by Glean’s Work AI Institute, results in two emerging behaviors: “botsitting,” all the unrecognized work that goes into making AI actually usable; and “botshitting,” shipping AI-generated work that is unverified, not that well understood, or perhaps not even trustworthy. The survey report was co-authored by experts from Work AI Institute, Emory University, Stanford University, UC Berkeley, UC Santa Barbara, UNC Charlotte, University College London, and University of Notre Dame.
“It’s definitely in many ways a vicious cycle that feeds itself,” said Rebecca Hinds, head of Glean’s research center the Work AI Institute, a research collaborative of AI experts. Enterprises need to begin understanding and addressing the “massive, massive human labor that’s at the core of this.”
Workers are using AI more, getting more frustratedThere’s no doubt that AI is quickly becoming a central teammate in the workplace. Glean’s Work AI Institute found that 87% of digital workers are using AI: It is already automating more than a quarter of their work and saving about 11 hours a week.
Still, only 13% say the use of AI has significantly improved their company’s performance, and their time savings are being eaten up by the same technology that is producing them. Employees lose about one-third of their work week (6.4 hours) botsitting: feeding AI context, supervising outputs, debugging errors, cleaning up AI-generated work, and switching between AI tools.
“We’re seeing high, high rates of multiple tool usage, and often those tools aren’t connected,” said Hinds.
In terms of context-feeding, large language models (LLMs) are trained on the vast corpus of the internet, but not always on enterprise-specific data. Thus, employees often have to provide additional information around their company’s products, customers, services, or other details.
“They’re often feeling frustrated when the tools don’t understand enough about day to day work to be useful,” said Hinds. Also, because employees are using multiple tools, they often have to repeat the same prompt over and over.
“It’s exhausting for workers to not only do this, but to have the work be unrecognized, often unrewarded and unacknowledged within the organization,” she said.
Similarly, workers are having to catch outputs that might look polished and finished on the surface, but could be wrong, incomplete, or missing important context. Debugging is the biggest driver of exhaustion, because it is often conducted by people who didn’t necessarily contribute to the initial output, Hinds noted, so they first have to dig up background information.
However, “not all botsitting is bad,” Hinds emphasized. “Certainly, we want workers to have some level of ownership and oversight.”
But when it is unnecessary, it can lead to botshitting, where users ship AI-generated work they haven’t verified because they’re overwhelmed or time-constrained. Sixty-nine percent of users admit to doing so, and 41% say they sometimes deliver work they could not explain if asked. Another 28% blame AI for mistakes they themselves caused.
“Botshitting is offloading your critical human thinking, judgment, and understanding,” Hinds explained. “You’re offloading that work that absolutely needs to remain with the human.”
Workers using multiple AI agents are significantly more likely to do this, she added, because agents are so scalable, and can spiral out of control if they don’t have the right controls or permissions built around them, causing overwhelmed users to give up on their verification efforts.
“You don’t often see the negative impacts until 3, 4, 5, steps down the line,” said Hinds. “Then it requires all of this cleanup work, detective work, to understand where did the agent go wrong.”
Using AI … but not too muchInterestingly, more than half of the workers surveyed said they get more day-to-day help from AI than they get from their managers, and consider it easier to collaborate with than humans.
Still, they seem to be facing a Goldilocks problem when it comes to sharing their use of AI. Among self-identified high AI achievers, 54% are using unapproved tools or using approved tools in noncompliant ways, and 36% are hiding how much AI helps them.
As Hinds explained, depending on the context and the level of psychological safety an organization has provided, it can be “differentially beneficial or harmful” to show you’re using AI, and, on the flip side, to conceal that you’re using it too much, because that might make you less valuable, or perceived as less valuable, she said.
It’s a complicated balance, because, she noted, “there’s massive pressure in so many organizations to demonstrate AI fluency, to demonstrate you’re a power user.”
What successful organizations are doing differentlyIn fact, the report said, “The companies pulling ahead are doing something different. They aren’t spending a greater share of their AI time using AI. They’re spending a greater share on the work around it: setting context, defining what ‘good’ looks like, building judgment, and deciding what should never have been handed to a model in the first place.”
The most transformative organizations are addressing AI challenges proactively: Providing training and support, treating AI as an opportunity to redesign work, and formally rewarding AI skills. In addition, it noted, the hardest skill to build is knowing when not to use AI.
It is “not just clicks of the tool, not just tokens used, but real skills, real learning,” said Hinds. In addition to investing in workers, these organizations are clearly stating AI strategy and clarifying the “why” behind it. Governance should also be “living and breathing,” with companies continuously re-evaluating policies.
And it needs to happen at every level, top execs included, said Hinds: “It’s being able to see the executives use the technology, sharing both the success stories and the failures.”
Successful companies are also actively using metrics anchored in existing key performance indicators (KPIs). They are measuring quality, efficiency, and employee engagement in different ways, and putting data in the hands of employees so they can assess their own adoption and success.
“It’s less about surveillance and more about feedback in terms of how we work collectively,” said Hinds.
What’s “fascinating but perhaps not surprising,” she said, is that workers are increasingly using AI itself as a teacher, and prefer it over other learning channels. This speaks to the importance of low-code, no-code tools, with low learning curves and organizational context, that are embedded directly into workflows.
“It is starkly different from what we’ve seen with previous technologies,” she said.
This article originally appeared on CIO.com.
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After Decades of Failure, ‘Undruggable’ Cancers Begin to Give Way
New drugs are taking on the slippery molecular switches that fuel deadly cancers—and AI is speeding up the hunt.
For decades, a handful of molecular switches has haunted the nightmares of cancer researchers. The switches trigger runaway tumor growth and cause the disease to spread across the body in multiple cancers. In theory, this makes them perfect treatment targets. Blocking even one could lead to drugs that are effective against a variety of cancers.
But despite considerable efforts, these switches—all of which are proteins—have escaped our most advanced cancer treatments, earning them the term “undruggable.” This is largely due to a shared trait: They all have smooth surfaces, making it difficult for drugs to interact with them.
But maybe not for much longer.
Researchers recently reported promising results for a new medication targeting a family of undruggable proteins in a clinical trial for advanced pancreatic cancer. The drug, daraxonrasib, nearly doubled survival time compared to chemotherapy, with fewer side effects. It’s not a total cure. But the treatment gives patients precious time, adding roughly 13 months after diagnosis. Patients also reported less pain and better quality of life.
Daraxonrasib is the latest in a new generation of drugs aimed at undruggable proteins. And AI-based tools are now poised to further accelerate progress in the field.
RAS AttackThe RAS family was the first group of oncogenes—or genes that drive cancer—ever discovered. The genes became a major focus in 1982 when several teams independently showed the mutation of a single DNA letter could transform RAS genes into a potent cancer trigger.
The proteins RAS genes encode are like spring-loaded molecular switches that relay signals from a cell’s surroundings. When proteins called growth factors latch onto a cell, RAS switches flip on to promote cell growth and survival, while built-in safeguards quickly turn them off again.
Cancerous mutations break this cycle. The switches get stuck in the “on” position, continuously instructing cells to grow and divide. This is, of course, a hallmark of cancer.
An ideal drug would simply switch RAS off. But most drugs are like rock climbers. They need grooves, pockets, or bumps on a protein to grab onto. Similar to a smooth rock face, RAS offers few such features. Making matters worse, different mutations subtly reshape the protein, so it’s tough to build a one-size-fits-all inhibitor.
The first RAS drug wasn’t approved in the US until 2021, nearly four decades after discovering the genes’ role in cancer. Even then, the drug targeted just one family member of three, limiting its reach to a relatively small group of patients. Many eventually developed resistance.
That’s why daraxonrasib turned heads. Developed by Revolution Medicines in Redwood City, California, the drugs switches off all three RAS family members. Rather than trying to grip the slippery proteins directly, it binds to a partner molecule that helps RAS proteins fold into their final 3D shapes. In this way, the drug hitches a ride on active RAS and shuts the proteins down.
The workaround paid off. The new study enrolled 500 people worldwide with advanced pancreatic cancer. All participants had already tried cancer therapies with limited success. On average, patients receiving daraxonrasib lived 13.2 months and spent most of that time with limited pain. The most common discomfort was a rash. Those receiving chemotherapy fared worse, living roughly 6.6 months and experienced more severe side effects.
The results don’t rival the dramatic success of CAR T cell therapies in blood cancer. In CAR T, caregivers engineer a patient’s own immune cells to recognize and attack tumors, sometimes producing long-lasting remission after a single infusion.
But the findings have energized the field. If approved, a daily daraxonrasib pill would likely be far more affordable and easier to administer than a personalized cell therapy. And because RAS mutations fuel many solid cancers—which CAR T still struggles to control—the drug could offer a new defense against deadly cancers that are largely beyond cell therapy’s reach. Combining daraxonrasib with earlier-generation RAS inhibitors may further boost its effects.
The Genome GuardianDaraxonrasib didn’t appear overnight. Scientists used a crystallized snapshot of its target protein as a molecular blueprint. Years of medicinal chemistry followed, with scientists repeatedly tweaking candidate compounds to boost potency, improve selectivity, and minimize toxicity.
AI could dramatically accelerate similar efforts against other undruggable cancer targets. Among the most coveted is p53, often called the “guardian of the genome” for its dizzying array of roles. The protein orchestrates the activity of over 300 genes involved in DNA repair, metabolism, cell death, and inflammation, making it one of the cell’s most important defense systems.
Since its discovery in 1979, p53 has been both a holy grail and a headache for cancer researchers. Mutations in the gene are common in multiple cancers. But like RAS, the protein is flat and smooth. Some mutations destabilize its structure; others turn it into misfolded clumps. A universal p53 drug has remained elusive.
Some researchers are trying to restore the protein. In a small trial earlier this year, they tested a drug that restabilizes a common mutant form of p53. Within 21 days, tumors shrank roughly 20 percent in patients with ovarian, breast, and several other solid cancers.
Other researchers aim to selectively kill cells carrying the mutation. Using AI, a team at Baylor College of Medicine screened nearly 10 million compounds that cause mutated p53 cells to self-destruct, while sparing healthy cells. The search uncovered 83 chemically distinct candidates. One called H3 dramatically suppressed tumor growth in mice.
“These results highlight the potential use of AI-powered drug screening to investigate individual p53 mutants in the future,” they wrote. Although the approach is early-stage and only focused on one mutation, the team is hopeful it can be extended to other cancerous mutations.
Most WantedMYC is another formerly undruggable protein that could now be vulnerable. Roughly 70 percent of cancers have abnormal MYC activity. Normally, the protein is a master regulator of growth, directing cells to manufacture proteins, replicate DNA, absorb nutrients, and divide when needed.
Cancer finds many ways to hijack the system and keep cells in a state of runaway growth. MYC gene mutations aren’t just single-letter swaps. Sometimes the gene duplicates or is rearranged across the genome, churning out excessive amounts of the protein it encodes. This genetic diversity makes approaches using gene therapy difficult. And again, like RAS, the MYC protein’s smooth, featureless surface lacks stable anchors for drugs.
An emerging strategy is to disrupt MYC’s interaction with other proteins that it needs to function. A designer protein blocking MYC activity, for example, recently showed promise in a small trial against solid cancers. Other teams are using AI to identify drugs that limit MYC’s ability to fix damaged DNA in tumors, kneecapping their ability to divide. Meanwhile, biotechnology companies are deploying AI to map out MYC’s structure and molecular interactions in search of new ways to shut the protein down.
Daraxonrasib’s success shows that undruggable proteins aren’t untouchable. There’s a lot more work ahead to prove other similar drugs can work too. But scientists are increasingly leaning into AI during all stages of drug development to speed up the process. Maybe, one day, “undruggable” will disappear from our vocabulary altogether.
The post After Decades of Failure, ‘Undruggable’ Cancers Begin to Give Way appeared first on SingularityHub.
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