Paolo Davide, CRUK Clinical Research Training Fellow at the University of Manchester and Medical Oncology Registrar, shared on LinkedIn:
“KRAS-mutant lung cancer: are all mutations created equal? We think not.
KRAS mutations drive ~30% of lung adenocarcinomas. The field is moving fast – divarasib became the first KRAS-targeting agent to show an overall survival benefit in NSCLC at ESMO 2026 – but that benefit was over first-generation G12C inhibitors, and the broader problem remains: most alleles have no selective agent, and resistance is near-universal.
In our review, just published in Biochemical Journal, we argue that each KRAS allele has its own biology and its own vulnerabilities:
- G12C -sensitive at multiple nodes: SHP2/SOS1 upstream, ON- and OFF-state KRAS inhibition, and downstream MAPK blockade.
- G12D – the most oncopotent allele studied, strongly PI3K-AKT-mTOR driven, with a more immunosuppressive TME and worse outcomes on PD-(L)1 therapy.
- G13C/G13D – GEF-dependent “hyper-exchange” mutants, relatively resistant to multi-selective RAS(ON) inhibition, and a plausible fit for OFF-state targeting; G13C is sensitive to multiple cytotoxics.
- Q61H – decoupled from RTK input, so resistant to upstream targeting; preferentially MAPK-driven, pointing to combinations across different nodes of the pathway.
Co-mutations are part of the allele’s identity. STK11, KEAP1 and NF1 cluster differently across alleles, and they modify drug response.
The most common KRAS allele is not the most oncopotent.
G12C is the most frequent KRAS mutation in NSCLC, but in carcinogen-driven and genetically engineered mouse models it is comparatively weakly oncogenic, while G12D is the most oncopotent.
Why does all this matter? There are far too many possible (K)RAS-inhibitor combinations to test them all in clinical trials.
Picking combination partners by allele is a more rational route to beating resistance.
We also tabulate every reported clinical trial of KRAS-targeting therapy in NSCLC to date, from sotorasib and adagrasib through to RAS(ON) inhibitors and degraders.
Proud to share co-first authorship with Will McDaid, alongside Kirsty Tinsley, Tong Chen and Emma Gasson, with Colin Lindsay and Angeliki Malliri as senior authors.”
About the Review
The review, “Uncovering KRAS-mutant allele-specific biology and vulnerabilities in non-small cell lung cancer,” was published in Biochemical Journal. Its authors are Paolo Davide d’Arienzo, William J. McDaid, Kirsten L. Tinsley, Tong Chen, Emma J. Gasson, Colin R. Lindsay and Angeliki Malliri.
The authors argue that KRAS-mutant NSCLC should not be treated as a single molecular entity. Instead, individual KRAS alleles differ in their biochemical properties, oncogenic potential, co-mutation patterns and therapeutic vulnerabilities, potentially supporting more allele-specific approaches to treatment and rational combination strategies.
Recent Phase 3 Krascendo 1 data further highlight the rapidly evolving KRAS landscape: divarasib improved median overall survival to 17.7 months versus 12.0 months with sotorasib or adagrasib in previously treated KRAS G12C-mutated NSCLC.“
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