Induced ERBB response and standing FAK dependency nominate separable KRAS-combination hypotheses in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS in roughly 90% of cases, and KRAS-pathway inhibition has finally become clinically active. Durable benefit, however, will require identifying the adaptive and baseline vulnerabilities that shape response to KRAS inhibition. Two resistance mechanisms have been proposed separately in the literature - receptor-tyrosine-kinase bypass of KRAS, and dependence on the adhesion kinase FAK - but whether they are one target class or two, and which should partner a KRAS inhibitor, is unresolved. We integrate public perturbation, dependency, and survival data to nominate them as mechanistically separable candidate combination partners. Two findings define the separation. First, KRAS loss increases ERBB2/3 receptor expression. This appeared in both an inducible genetic KRAS-extinction model and, independently, in five PDAC lines treated with pharmacological KRAS-G12C/D inhibitors, while MAPK output collapsed as expected. The signal was clearest for ERBB2 and in the genetic model; in the small pharmacological cohort the effect was modest and its confidence intervals crossed zero, so we treat ERBB2/3 up-regulation as a candidate adaptive response - ERBB2-dominant and ERBB3-compatible - not a proven resistance mechanism. Second, focal adhesion kinase (FAK/PTK2) is the top-ranked standing druggable dependency within the KRAS/Src/RTK/adhesion network we examined (essential in 58% of pancreatic lines), yet it is not induced by KRAS shutdown. FAK dependency is present at baseline and, in DepMap, is statistically independent of a line's KRAS dependency (Spearman ρ = +0.05, n.s.) - a genuinely standing vulnerability rather than a KRAS-rebound effect. The candidate adaptive response and the standing dependency are not positively co-regulated across the perturbed lines (pooled Spearman ρ = -0.43, but n = 8 and n.s., so this cannot by itself establish independence); we therefore treat them as separable on mechanistic grounds - each nominated by different data and engaged by a different drug - rather than as statistically demonstrated independent programs. A Src-centered signaling-landscape analysis associates patient prognosis with the coordinated invasion-and-RTK program these nodes organize, rather than with any single transcript; this program remains prognostic after adjustment for a conventional EMT/stromal signature, which does not (Src-neighborhood per-standard-deviation OS hazard ratio 1.9, p ≈ 3 × 10⁻⁵; EMT signature null on adjustment). Together these results motivate a concrete, testable hypothesis: that FAK inhibition (a standing dependency) and ERBB inhibition (a candidate induced adaptive response) are separable candidate partners for a KRAS inhibitor, best evaluated as distinct arms of a biomarker-stratified platform. They also clarify why single-agent Src inhibition - a non-oncogene dependency tested as monotherapy, without a KRAS backbone, in advanced rather than micro-metastatic disease - was not positioned to surface either mechanism. No protein-level, phospho-signaling, or combination-response validation is performed here; all findings are computational nominations that require experimental validation before any clinical inference.

KRAS inhibition is associated with an induced ERBB2/3 up-regulation - ERBB2-dominant, ERBB3-compatible - directionally reproduced across genetic KRAS extinction and pharmacological KRAS-G12C/D inhibition; the pharmacological effect is modest and underpoweredGenome-wide dependency nominates FAK - essential in 58% of pancreatic lines - as the top-ranked standing candidate co-target within the KRAS network; FAK dependency is present at baseline, statistically independent of KRAS dependency, and not co-regulated with the induced ERBB response Patient prognosis associates with a Src-organized invasion-and-RTK program, not with SRC , KRAS , or any single-gene transcript, and this program stays prognostic after adjustment for a conventional EMT/stromal signature The two mechanisms are separable on mechanistic grounds - nominated by different data and not positively co-regulated (though the direct correlation is underpowered, n = 8, n.s.) - motivating a multi-arm platform that could test FAK and ERBB partner arms as distinct hypotheses rather than one bundled combination.

Blocking KRAS in pancreatic cancer is now clinically feasible, but resistance is the obstacle. Using only public data, Chen and colleagues nominate two mechanistically separable candidate combination partners for KRAS inhibitors: a candidate ERBB2-dominant adaptive (putative escape) response that is induced when KRAS is blocked, and FAK, the top-ranked standing dependency in the KRAS network - present at baseline and independent of a tumor's KRAS dependency. Because the two are nominated by different data and are not positively co-regulated, they argue for a multi-arm KRAS-combination trial that tests each as a separate hypothesis - and they explain why the earlier single-agent Src trials, run without a KRAS backbone and in the wrong disease setting, were not positioned to detect either. The findings are computational nominations that require experimental validation.