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

By F. Skoulidis, L. Byers, L. Diao, V. Papadimitrakopoulou, P. Tong, J. Izzo, C. Behrens, H. Kadara, E. Parra, J. R. Canales and 27 more. Cancer Discovery, 2015

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The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma (LUAC) are poorly characterized. We performed an integrative analysis of genomic, transcriptomic and proteomic data from early-stage and chemo-refractory LUAC and identified three robust subsets of KRAS-mutant LUAC dominated, respectively, by co-occurring genetic events in STK11/LKB1 (the KL subgroup), TP53 (KP) and CDKN2A/B inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). We further reveal biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC1 signaling. KL tumors had high rates of KEAP1 mutational inactivation and expressed lower levels of immune markers, including PD-L1. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of KRAS-mutant LUAC with distinct biology and therapeutic vulnerabilities.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/a643b2b8206d3ac014ad901f3fc4b27f1c13e2e5

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Citations in the corpus

Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. (2018, background): “of patients 240 759 Median age, years (range) 66 (22-92) 66 (22-93) .”
Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, background): “STK11 was exclusively associated with resistance, which aligns with previous reports describing the T cell excluded phenotype associated with these variants (Skoulidis et al., 2015), but did not reach statistical significance.”
STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma (2018, background): “4% in the combined FM/SU2C cohort) and foster establishment of a non-T cell–inflamed tumor immune microenvironment with frequently undetectable tumor cell PD-L1 expression (18, 20, 21).”