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Lung cancers driven by a mutated KRAS gene behave so differently from one another that they are better thought of as three diseases, and which of the three a patient has depends on the second gene that is broken.
An integrative analysis of genomic, transcriptomic and proteomic data from early-stage and chemorefractory lung adenocarcinoma identified three robust subsets of KRAS-mutant disease, dominated respectively by co-occurring events in STK11 or LKB1 (the KL subgroup), TP53 (KP) and CDKN2A or CDKN2B inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). KC tumours frequently showed mucinous histology and suppressed mTORC1 signalling. KL tumours had high rates of KEAP1 inactivation and expressed lower levels of immune markers including PD-L1. KP tumours had higher somatic mutation levels, inflammatory markers, immune checkpoint effector molecules and improved relapse-free survival. Drug sensitivity also differed, with KL cells showing increased vulnerability to HSP90 inhibition.
It is the origin of the idea, now central to lung oncology, that the co-mutation and not the driver decides how a KRAS-mutant tumour behaves and whether immunotherapy will work.
Shares Ferdinandos Skoulidis, STK11 / KEAP1 co-mutations, KEAP1-NRF2 antioxidant pathway, KEAP1.
Shares STK11 / KEAP1 co-mutations, KEAP1-NRF2 antioxidant pathway, KEAP1, STK11.
Shares STK11 / KEAP1 co-mutations, KEAP1, Cancer Discovery, STK11.
Shares STK11 / KEAP1 co-mutations, KEAP1-NRF2 antioxidant pathway, KEAP1, STK11.
Shares STK11 / KEAP1 co-mutations, KEAP1, Cancer Discovery, STK11.
Shares NKX2-1, KEAP1-NRF2 antioxidant pathway, KEAP1, STK11.
Shares STK11 / KEAP1 co-mutations, KEAP1, STK11, T-cell exhaustion.
Shares STK11 / KEAP1 co-mutations, KEAP1, STK11, PD-L1.