About a quarter of lung adenocarcinomas carry KRAS mutations that drive uncontrolled growth. The FDA has approved two KRAS‑G12C inhibitors for patients with these mutations; they work well at first but resistance almost always emerges. The usual routes involve re‑activating KRAS—either through secondary mutations that block drug binding or by amplifying KRAS expression, which overwhelms the inhibitor and re‑engages the MAPK pathway.
A new MIT study modeled an alternative resistance route: after KRAS‑G12C inhibition, some lung tumors switch histologically from adenocarcinoma to squamous cell carcinoma. Although both tumor types are common in the lung, they arise from different cells and have distinct genetic profiles. Once the switch occurs, the tumors no longer depend on KRAS and appear to turn on other signaling pathways to keep growing. In a mouse model engineered to express KRAS‑G12C, tumors lacking the lineage factor Nkx2‑1 readily underwent the adeno‑to‑squamous transition. Over‑expression of the transcription factor DeltaNp63 further promoted this change, while SOX2 also contributed but could not initiate the switch alone.
These transformed tumors did not acquire the typical KRAS amplifications or secondary mutations; KRAS signaling was essentially shut down. The authors hypothesize that an alternative pathway sustains proliferation, and they are now probing the squamous state to uncover vulnerabilities that could be targeted with new drugs, aiming to prevent or overcome resistance.
The work was funded by the MIT Koch Institute, the National Cancer Institute, and other grants, and appears in Nature Genetics.
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