{"entity":{"id":"paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015","kind":"paper","name":"Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-25","links":[{"label":"Skoulidis et al., Cancer Discov 2015: co-occurring alterations define the KL, KP and KC subsets of KRAS-mutant lung adenocarcinoma","url":"https://doi.org/10.1158/2159-8290.CD-14-1236"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26069186/"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":["rna-seq","cgp"],"targets":["kras","stk11","tp53","cdkn2a","nkx2-1","keap1","pdl1"],"drugs":[],"companies":[],"institutions":["md-anderson"],"pathways":["ras-mapk","t-cell-exhaustion","keap1-nrf2","pi3k-akt-mtor"],"terms":["kras-mutation-subtypes","stk11-keap1","cold-vs-hot"],"trials":[],"people":["ferdinandos-skoulidis"],"bottlenecks":[],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2015,"doi":"10.1158/2159-8290.CD-14-1236","pmid":"26069186","authors":"Skoulidis F, Byers LA, Diao L, et al.","paperType":"translational","findings":["Three subgroups of KRAS-mutant lung adenocarcinoma: KL, KP and KC.","KL tumours are immune-poor with low PD-L1 and frequent KEAP1 loss.","KP tumours are inflamed, more mutated and have better relapse-free survival.","KC tumours are mucinous with suppressed mTORC1 signalling."],"whatItMeans":"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.","caveats":["Derived from expression and proteomic clustering, so subgroup boundaries depend on the method.","Drug sensitivity findings are preclinical.","No prospective trial has randomised on these subgroups."],"changedPractice":false},"route":"/key-papers/paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"}],"target":[{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"keap1","kind":"target","name":"KEAP1","route":"/targets/keap1/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"nkx2-1","kind":"target","name":"NKX2-1","route":"/targets/nkx2-1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"},{"id":"stk11","kind":"target","name":"STK11","route":"/targets/stk11/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"}],"pathway":[{"id":"keap1-nrf2","kind":"pathway","name":"KEAP1-NRF2 antioxidant pathway","route":"/pathways/keap1-nrf2/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"t-cell-exhaustion","kind":"pathway","name":"T-cell exhaustion","route":"/pathways/t-cell-exhaustion/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"kras-mutation-subtypes","kind":"term","name":"KRAS mutation subtypes (G12C, G12D, G12V)","route":"/terms/kras-mutation-subtypes/"},{"id":"stk11-keap1","kind":"term","name":"STK11 / KEAP1 co-mutations","route":"/terms/stk11-keap1/"}],"person":[{"id":"ferdinandos-skoulidis","kind":"person","name":"Ferdinandos Skoulidis","route":"/people/ferdinandos-skoulidis/"}],"journal":[{"id":"cancer-discovery","kind":"journal","name":"Cancer Discovery","route":"/journals/cancer-discovery/"}]}}