The Scientific Case For A Revolution Medicines And Kymera Therapeutics Partnership

Disclosure: The author holds beneficial long positions in Kymera Therapeutics, Inc. (NASDAQ: KYMR) and Revolution Medicines, Inc. (NASDAQ: RVMD). This article is for informational and educational purposes only and does not constitute financial advice. While the author is a medical doctor, the views expressed here represent a personal opinion regarding the science and market potential of these companies and are not medical advice, diagnosis, or treatment recommendations. Specifically, the discussion regarding a partnership between these companies is speculative and hypothetical. The author receives no compensation for this article and has no business relationship with the companies mentioned. Please see the full "Legal Information and Disclosures" section below.

Recent research from Mariano Barbacid’s laboratory at Spain's National Cancer Research Centre (CNIO), published in PNAS in December 2025, has introduced a potentially transformative approach to treating pancreatic ductal adenocarcinoma (PDAC). The study demonstrated complete and durable tumor regression in mouse models using a triple combination therapy targeting KRAS, EGFR, and STAT3 simultaneously. Although pre-clinical results require cautious interpretation, these findings could provide a scientific rationale for a potential collaboration between Revolution Medicines (NASDAQ: RVMD) and Kymera Therapeutics (NASDAQ: KYMR) to bring this concept to human trials.

The premise of this combination is the critical need to overcome the adaptive resistance that limits current therapies. Revolution Medicines has finally achieved targeting KRAS in PDAC with its leading candidate, daraxonrasib, a RAS(ON) multi-selective inhibitor that blocks KRAS in its active state. Since more than 90% of PDAC tumors harbor KRAS mutations, this represents a breakthrough in treatment. However, PDAC cells are notoriously plastic, rapidly rewiring their signaling networks to escape single-agent attacks.

Mariano Barbacid's research identified the specific escape routes. When KRAS and its upstream activator, EGFR, are blocked, tumor cells activate a backup survival pathway mediated by the transcription factor STAT3. This resistance loop allows the cancer to persist despite inhibition of its primary driver. By targeting STAT3 alongside KRAS and EGFR inhibition, the researchers effectively closed this escape route. The triple combination induced complete tumor regression in orthotopic mouse models and patient-derived xenografts, with no evidence of resistance for over 200 days.

Like KRAS, STAT3 has long been considered an undruggable target because it lacks the enzymatic pockets that conventional small molecules typically bind. The study employed SD-36, a PROTAC degrader that recruits the Cereblon E3 ligase to tag STAT3 for proteasomal destruction. This complete removal is often necessary to disrupt the non-canonical signaling and scaffolding roles that sustain cancer cell survival.

However, SD-36 is a chemical probe optimized for laboratory research, not a clinical candidate. Kymera's KT-333 is currently the only highly selective heterobifunctional STAT3 degrader to have entered human trials. Unlike SD-36, which recruits Cereblon, KT-333 recruits the Von Hippel-Lindau (VHL) E3 ligase. KT-333 has demonstrated substantial STAT3 degradation in patients and produced complete responses in two of three relapsed/refractory classical Hodgkin's lymphoma patients during its Phase 1 study. However, Kymera announced in late 2024 that it would shift resources toward its immunology pipeline and would only advance KT-333 beyond Phase 1 with a partner. Consequently, this asset is clinically validated but sitting idle.

The CNIO researchers tested daraxonrasib as the KRAS inhibitor and afatinib, an irreversible pan-ERBB inhibitor already approved for lung cancer, as the EGFR blocker. Replacing SD-36 with KT-333 would create a triple combination using two human-ready molecules and one already on the market.

That said, translating these preclinical results to patients will not be straightforward. Even assuming the triple combination prevents resistance in human pancreatic cancer, these agents must first penetrate the tumors. A hallmark of human PDAC is its dense desmoplastic stroma, a fibrotic barrier that shields cancer cells from therapeutics and creates interstitial pressures that impair drug delivery. Mouse models do not replicate this challenge accurately. The diffusion distances in a millimeter-scale mouse tumor differ drastically from those in a centimeter-scale mass that can comprise up to 80% stroma.

Because of this biological barrier, systemic therapy alone is unlikely to cure advanced pancreatic cancer. Surgical resection combined with neoadjuvant, perioperative, or adjuvant treatment will most likely remain the only realistic path to a cure. The goal of drug therapy is to shrink tumors, sterilize margins, enable successful surgery, and prevent relapse, but current regimens often lose effectiveness within months as resistance emerges. This is precisely the context where the Barbacid combination could prove valuable.

Revolution Medicines is actively advancing daraxonrasib through multiple Phase 3 trials. RASolute 302 is evaluating the drug as monotherapy in previously treated metastatic PDAC, with a data readout anticipated in 2026. The company has also initiated trials in the first-line and adjuvant settings. However, resistance is the Achilles' heel of targeting KRAS. If STAT3 activation represents a dominant resistance mechanism, adding a STAT3 degrader could substantially extend the duration of tumor control.

Overcoming resistance with this combination requires clinical validation beyond mouse models and must demonstrate manageable toxicity when three agents are combined. Neither is guaranteed. Specifically, both daraxonrasib and afatinib are associated with cutaneous toxicities; managing the cumulative burden of rash will be critical in a human triple regimen. However, Kymera's Phase 1 data show that KT-333 is well tolerated at doses achieving substantial target degradation, and the individual toxicity profiles of daraxonrasib and afatinib are well understood.

Mariano Barbacid himself has emphasized that clinical trials with this exact triple therapy are not imminent, partly because SD-36 has no regulatory path forward. However, a collaboration between Revolution Medicines and Kymera could substitute KT-333 for the preclinical STAT3 degrader and move the concept toward patients. Revolution Medicines has the financial resources and regulatory momentum in pancreatic cancer. Kymera holds a stranded asset that matches the biological requirement. The critical question is whether either company sees sufficient strategic value to pursue it.

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Legal Information and Disclosures

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Disclosure of Interest: The author holds beneficial long positions in Kymera Therapeutics, Inc. (NASDAQ: KYMR) and Revolution Medicines, Inc. (NASDAQ: RVMD). The author reserves the right to buy or sell these securities at any time without further notice. The author receives no direct compensation for the production of this content and maintains no business relationship with the companies mentioned.

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