Blockade of the KRAS-FOSL1 axis elicits DNA damage repair deficiency exploitable with local and systemic genotoxic therapies

Blockade of the KRAS-FOSL1 axis elicits DNA damage repair deficiency exploitable with local and systemic genotoxic therapies | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Blockade of the KRAS-FOSL1 axis elicits DNA damage repair deficiency exploitable with local and systemic genotoxic therapies Silve Vicent, Connor Welch, Gabriela Novoa-Jaso, Carlos Vasquez-Valencia, and 27 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9085811/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The clinical approval of direct KRAS inhibitors represents a milestone in precision oncology. Nonetheless, resistance heterogeneity limits durable clinical responses and impedes the nomination of a ‘‘one-size-fits-all’’ strategy for combination therapies. We circumvent this impasse by uncovering a core vulnerability elicited by KRAS blockade which transcends tissue origin, KRAS mutation, intrinsic KRASi sensitivity, and clinically relevant concurrent mutations. Specifically, we show that KRAS inhibition elicits a functional deficit in DNA damage repair by transcriptionally repressing homologous recombination. This BRCAness phenotype constitutes a conditional synthetic lethality to PARP inhibitors and radiotherapy, which synergize with single KRAS blockade and significantly delay the onset of secondary resistance. Integrative analyses identify the transcription factor FOSL1 as an upstream regulator of homologous recombination whose depletion sensitizes to PARP inhibition and radiotherapy. Collectively, we define a translational trajectory for the combination of KRAS inhibitors with clinically approved DNA-damaging agents as a therapeutic strategy treatment potentially expandable to most, if not all, mutant KRAS cancers. Biological sciences/Cancer/Cancer therapy/Targeted therapies Biological sciences/Cancer/Oncogenes Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer Biological sciences/Cancer/Gastrointestinal cancer/Pancreatic cancer KRAS lung cancer pancreatic cancer DNA damage repair homologous recombination PARP inhibitor radiotherapy drug tolerant cells Full Text Additional Declarations Yes there is potential Competing Interest. S.V. has received research funding unrelated to this project and consulting fees from Revolution Medicines, additional funding for unrelated work from Roche, Verastem Oncology, and BridgeBio, and is a scientific advisor for Libera Bio. F.L. has received funding for unrelated work from Roche. A.B. reports receipt of grants/research supports from Neophore. A.B. is stock shareholder of Neophore and Kither Biotech. A.B. is advisory boards member for Neophore. Supplementary Files WelchetalSupplementaryInformationv7.docx Supplementary Information SupplTable1H358HPAFIILKR10RNAseq.xlsx Dataset 1 SupplTable2HUCCT1KKU213AKPchFC1242KLARNAseq.xlsx Dataset 2 SupplTable3LymphNodesRNAseq.xlsx Dataset 3 SupplTable4IntegrativeAnalysis.xlsx Dataset 4 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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