Overview
- The study, published May 21 in Cancer Cell, profiled patient‑matched biopsies before, during, and after KRAS‑inhibitor therapy using targeted sequencing and single‑cell spatial transcriptomics.
- Investigators found two distinct resistance pathways: rare genetic changes such as KRAS copy gains or secondary mutations and a widespread, early inflammatory cell‑state shift in malignant cells.
- Organoid experiments showed the same early inflammatory gene program in tumor cells grown without immune cells, indicating the response can originate inside cancer cells.
- A drug screen nominated the kinase TBK1 as a mediator of the inflammatory adaptation and combining TBK1 inhibition with KRAS blockers slowed tumor growth in organoid and patient‑derived models.
- The TBK1 plus KRAS inhibitor approach is preclinical and requires clinical trials to test safety, dosing, and whether the combination improves and prolongs patient responses to KRAS drugs.