# Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities

Source: https://onco.cc/key-papers/paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015/  
OnCo record `paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Cancer Discovery
- Year: 2015
- DOI: 10.1158/2159-8290.CD-14-1236
- Authors: Skoulidis F, Byers LA, Diao L, et al.
- 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.
- What it means: 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.

## Sources

- Skoulidis et al., Cancer Discov 2015: co-occurring alterations define the KL, KP and KC subsets of KRAS-mutant lung adenocarcinoma: https://doi.org/10.1158/2159-8290.CD-14-1236
- PubMed: https://pubmed.ncbi.nlm.nih.gov/26069186/

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [RNA sequencing & expression profiling](https://onco.cc/technologies/rna-seq/)
- targets: [CDKN2A](https://onco.cc/targets/cdkn2a/), [KEAP1](https://onco.cc/targets/keap1/), [KRAS](https://onco.cc/targets/kras/), [NKX2-1](https://onco.cc/targets/nkx2-1/), [PD-L1](https://onco.cc/targets/pdl1/), [STK11](https://onco.cc/targets/stk11/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [MD Anderson Cancer Center](https://onco.cc/institutions/md-anderson/)
- pathways: [KEAP1-NRF2 antioxidant pathway](https://onco.cc/pathways/keap1-nrf2/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [T-cell exhaustion](https://onco.cc/pathways/t-cell-exhaustion/)
- terms: [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [KRAS mutation subtypes (G12C, G12D, G12V)](https://onco.cc/terms/kras-mutation-subtypes/), [STK11 / KEAP1 co-mutations](https://onco.cc/terms/stk11-keap1/)
- people: [Ferdinandos Skoulidis](https://onco.cc/people/ferdinandos-skoulidis/)
- journals: [Cancer Discovery](https://onco.cc/journals/cancer-discovery/)

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