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Preprint WatchModerateSeptember 29th, 2026

Pathway-wide base editing charts chemical-genetic interactions in MAPK signaling

Woods, J.; Hu, C. X. Y.; Jang, D. M.; Freedman, C.; Canarelli, S.; Kwok, H. S.; Iram, I.; Eck, M. J.; Liau, B.

Pathway-wide CRISPR base editor scanning across 22 MAPK genes maps chemical-genetic interactions, identifies an allosteric site in the KRAS N-terminus, and shows that drug resistance mutations frequently arise in proteins other than the direct drug target.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that resistance to MAPK pathway drugs often arises in pathway proteins other than the direct target, and nominates an allosteric site in the KRAS N-terminus as an underappreciated functional hotspot. Claidex holds two KRAS failures: bgb-53038-kras-solid-tumors-phase1-strategic-reprioritization, a Phase 1 pan-KRAS programme stopped for portfolio reasons, and sotorasib-durvalumab-kras-g12c-ctdna-stage3-nsclc-phase2-enrollment-collapse, a Phase 2 stopped on accrual. Severity is MODERATE on failure count alone, and neither archetype is an efficacy failure, so the graph carries no evidence against KRAS as a target. The finding that bears on future design is the off-target resistance result: trials selecting patients on the mutation status of the drug's own target may misclassify resistance that originates elsewhere in the cascade, which is a testable claim rather than an established clinical one.

Abstract excerpt

CRISPR base editor (BE) scanning enables sequence-level interrogation of proteins at scale in their native cellular and genomic contexts. This approach opens new opportunities to dissect cellular pathways, where signaling depends on coordinated interactions among multiple pathway proteins. We apply BE scanning to the RAS-RAF-MEK-ERK (MAPK) cascade, a central oncogenic pathway and major therapeutic target. Compounds targeting the MAPK pathway have mechanisms of action and resistance that remain incompletely characterized. By base editing 22 MAPK genes under either hyperactivation or inhibition at various nodes, we present a chemical-genetic map of the signaling pathway. Pathway-wide analysis shows that drug resistance mutations frequently occur in proteins other than the direct drug target itself, and we exploit these chemical-genetic interactions to recapitulate key pathway connections. Our BE scanning also identified underappreciated functional hotspots, including an allosteric site in the KRAS N-terminus. We also identify catalytically impaired CRAF mutants that confer bidirectional resistance and sensitization to structurally similar MEK inhibitors, distinguishing functional differences between structurally related compounds. These findings establish BE scanning as a scalable approach for network-level chemical-genetic interaction mapping, revealing new mechanistic insights into one of the most studied oncogenic pathways.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.