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The race to drug KRAS in pancreatic cancer

The race to drug KRAS in pancreatic cancer

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By Newzino Staff | |

After 40 Years of 'Undruggable' Status, Scientists Zero in on the Oncogene Behind 90% of Cases

January 28th, 2026: Triple Therapy Achieves Complete Tumor Elimination

Overview

For 40 years, the KRAS gene has been oncology's white whale—present in 90% of pancreatic cancers, yet resistant to every drug thrown at it. Scientists called it 'undruggable.' On January 28, 2026, Spanish researchers published results showing they had achieved what decades of effort could not: complete and lasting tumor elimination in mice using a triple-drug combination that blocks KRAS and two downstream pathways simultaneously.

The stakes are enormous. Pancreatic cancer kills 87% of patients within five years, making it the deadliest major cancer. The disease is on track to become the second-leading cause of cancer death in the United States. While KRAS inhibitors like daraxonrasib are showing promise as single agents—nearly doubling median survival from 7 to 15.6 months in early trials—resistance inevitably emerges. If the triple therapy translates to humans, blocking three pathways at once could prevent that resistance and transform a death sentence into something treatable.

Key Indicators

90%
KRAS Mutation Rate
Share of pancreatic ductal adenocarcinomas driven by KRAS mutations
13%
5-Year Survival
Current survival rate for pancreatic cancer—the lowest of any major cancer
9 of 12
Complete Regression
Genetically modified mice achieving full tumor elimination with triple therapy
250+ days
Tumor-Free Survival
Duration mice remained cancer-free after treatment in implanted tumor model

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Oscar Wilde

Oscar Wilde

(1854-1900) · Victorian · wit

Fictional AI pastiche — not real quote.

"How delightful that Science, having spent forty years declaring something impossible, has finally succeeded by the simple expedient of trying three times as hard—a strategy that would have saved many a Victorian marriage, had anyone thought to apply it. One does hope the mice appreciate being cured of their mortality, though I suspect they would have preferred never to have been given cancer in the first place."

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People Involved

Mariano Barbacid
Mariano Barbacid
Director, Experimental Oncology Group at CNIO (Leading triple therapy research toward clinical trials)
Carmen Guerra
Carmen Guerra
Staff Scientist at CNIO, Co-Senior Author (Active researcher on triple therapy development)

Organizations Involved

Spanish National Cancer Research Centre (CNIO)
Spanish National Cancer Research Centre (CNIO)
Research Institution
Status: Conducting preclinical research, seeking path to human trials

Spain's national cancer research center, ranked among the top 15 cancer research institutions globally.

Revolution Medicines
Revolution Medicines
Biotechnology Company
Status: Daraxonrasib in Phase 3 trials (RASolute 302 readout expected 2026); acquisition talks with Merck collapsed January 2026

Developed daraxonrasib (RMC-6236), the KRAS inhibitor used in the Spanish triple therapy study.

CRIS Against Cancer Foundation
CRIS Against Cancer Foundation
Non-Profit Research Funder
Status: Primary funder of Barbacid's pancreatic cancer research

Spanish foundation that funded six years of triple therapy development at CNIO.

Timeline

  1. Triple Therapy Achieves Complete Tumor Elimination

    Research

    CNIO publishes PNAS study showing complete and lasting pancreatic tumor elimination in mice using daraxonrasib plus afatinib plus SD-36. Nine of 12 genetically modified mice achieved full regression; implanted tumor models remained cancer-free for 250+ days.

  2. Merck Acquisition Talks Collapse

    Business

    Negotiations between Merck and Revolution Medicines over a potential $28-32 billion acquisition ended without agreement on price. Revolution Medicines stock dropped 20% following the announcement, erasing nearly $6 billion in market value.

  3. Merck Enters Acquisition Talks

    Business

    Financial Times reports Merck in talks to acquire Revolution Medicines for $28-32 billion, potentially making it the largest biotech deal since Pfizer's $43 billion Seagen acquisition in 2023. Stock surged 20% on the news.

  4. Daraxonrasib Monotherapy Shows Survival Gains

    Research

    Early reporting from Phase 1 trials shows daraxonrasib nearly doubles median survival to 15.6 months compared to 7 months with standard chemotherapy, with more than 90% of 83 patients experiencing disease stabilization and roughly 30% seeing tumor shrinkage.

  5. Daraxonrasib Receives Orphan Drug Status

    Regulatory

    FDA grants Orphan Drug Designation to daraxonrasib for pancreatic cancer treatment, providing additional development incentives.

  6. Daraxonrasib Gets Breakthrough Designation

    Regulatory

    FDA grants Breakthrough Therapy Designation to daraxonrasib (RMC-6236), a multi-selective KRAS inhibitor that targets mutations common in pancreatic cancer, based on promising Phase 1 data showing 8.8-month progression-free survival.

  7. Second KRAS Inhibitor Approved

    Regulatory

    FDA approves adagrasib (Krazati) for KRAS G12C-mutated lung cancer, providing a second option but still not addressing the G12D mutations dominant in pancreatic cancer.

  8. First KRAS Inhibitor Approved

    Regulatory

    FDA grants accelerated approval to sotorasib (Lumakras) for KRAS G12C-mutated lung cancer—the first approved drug targeting any KRAS mutation after 40 years of failed attempts. However, G12C mutations are rare in pancreatic cancer.

  9. SD-36 STAT3 Degrader Published

    Research

    University of Michigan researchers publish SD-36, a PROTAC degrader that selectively destroys STAT3 protein. The compound achieves complete tumor regression in mouse models of leukemia and lymphoma.

  10. Afatinib Approved for Lung Cancer

    Regulatory

    FDA approves afatinib (Gilotrif), an irreversible EGFR inhibitor, for metastatic non-small cell lung cancer. This drug would later become one of three components in the CNIO triple therapy.

  11. First Human Oncogene Isolated

    Discovery

    Three independent research groups, including Barbacid's, identify HRAS as the first human oncogene. The discovery establishes RAS proteins as central to cancer but also reveals how difficult they are to drug.

Scenarios

1

Triple Therapy Advances to Human Trials by 2029

Discussed by: CNIO researchers in PNAS publication and press statements

If funding materializes and regulatory approvals proceed smoothly, clinical trials combining daraxonrasib, afatinib, and a STAT3 degrader could begin within three years, as Barbacid projects. This depends on Revolution Medicines and other parties agreeing to combination studies, SD-36 or a similar STAT3 degrader advancing through safety testing, and sufficient patient enrollment. Success would still require years of trials before any approval.

2

Daraxonrasib Monotherapy Approved, Combination Delayed

Discussed by: Revolution Medicines investor communications, oncology analysts

Revolution Medicines is already pursuing FDA approval for daraxonrasib as a single agent, with Phase 3 readouts expected in 2026. If approved, daraxonrasib could reach patients for second-line pancreatic cancer treatment while triple-combination trials proceed separately. This scenario would deliver incremental benefit—likely extending survival by months rather than achieving the complete responses seen in mice.

3

Resistance Mechanisms Emerge in Human Trials

Discussed by: Oncology researchers, Cancer Biology & Medicine review articles

KRAS inhibitors consistently generate resistance in human patients, driven by secondary mutations, pathway reactivation, and metabolic adaptations. The triple therapy is designed to prevent resistance by blocking three points simultaneously, but human tumors are more heterogeneous than mouse models. If resistance emerges despite triple blocking, researchers would need to identify fourth or fifth targets.

4

Mouse Results Fail to Translate to Humans

Discussed by: Cancer research community broadly, historical precedent

Most cancer treatments that work in mice fail in human trials. Genetically engineered mouse models like those used at CNIO are considered more predictive than simple xenografts, but the gap between complete mouse regression and meaningful human survival extension remains vast. If Phase 1 human studies show insufficient efficacy or unacceptable toxicity, the triple combination could stall indefinitely.

Historical Context

Imatinib and Chronic Myeloid Leukemia (2001)

May 2001

What Happened

The FDA approved imatinib (Gleevec) for chronic myeloid leukemia, the first cancer drug designed to target a specific molecular defect—the BCR-ABL fusion protein. Patients who had months to live began achieving long-term remission. The drug transformed CML from a death sentence into a manageable chronic condition.

Outcome

Short Term

Five-year survival for CML patients jumped from 30% to over 90%.

Long Term

Imatinib became the template for targeted cancer therapy, proving that attacking specific oncogenic drivers could succeed where chemotherapy failed.

Why It's Relevant Today

KRAS researchers explicitly cite imatinib as their model. Like BCR-ABL, KRAS drives cancer growth; unlike BCR-ABL, KRAS resisted drugging for 20 additional years. The CNIO triple therapy aims to achieve for pancreatic cancer what imatinib did for CML.

EGFR Inhibitors in Lung Cancer (2003-2013)

2003-2013

What Happened

After early EGFR inhibitors showed mixed results in unselected lung cancer patients, researchers discovered that only tumors with specific EGFR mutations responded. Gefitinib (2003) and erlotinib (2004) were approved for mutation-positive patients, followed by afatinib (2013). However, resistance typically emerged within 12-18 months.

Outcome

Short Term

EGFR-mutant lung cancer patients gained months to years of progression-free survival.

Long Term

The resistance problem drove development of next-generation inhibitors and combination strategies—the same approach now being applied to KRAS.

Why It's Relevant Today

Afatinib, one of the three drugs in the CNIO combination, was designed to overcome resistance to earlier EGFR inhibitors. The triple therapy strategy—blocking the primary driver plus escape routes—directly responds to lessons learned from EGFR resistance.

KRAS G12C Breakthrough (2021)

May 2021

What Happened

After researchers discovered a previously unknown binding pocket on the KRAS G12C mutant protein, Amgen developed sotorasib—the first approved drug targeting any KRAS mutation. The FDA granted accelerated approval based on a 36% response rate in lung cancer patients who had failed other treatments.

Outcome

Short Term

Patients with G12C mutations gained a new treatment option, though responses were often temporary.

Long Term

The approval proved KRAS was druggable after all, triggering massive investment in inhibitors targeting other KRAS mutations.

Why It's Relevant Today

Sotorasib's approval validated the KRAS-targeting approach but left pancreatic cancer patients behind—G12C mutations occur in only 1-2% of pancreatic tumors versus 40% for G12D. The CNIO study uses daraxonrasib, which targets the mutations actually common in pancreatic cancer.

17 Sources:
+11
Euronews Ara PNAS CNIO Revolution Medicines Pancreatic Cancer Action Network National Cancer Institute CRIS Cancer Cancer Cell Lustgarten Foundation AI Invest FinancialContent Bloomberg Yahoo Finance El Independiente The Spokesman-Review Medical Xpress