Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
Top Cited Papers
- 1 August 2015
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 5 (8), 860-877
- https://doi.org/10.1158/2159-8290.cd-14-1236
Abstract
The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets of KRAS-mutant lung adenocarcinoma 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 revealed 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 lung adenocarcinoma with distinct biology and therapeutic vulnerabilities. Significance: Co-occurring genetic alterations in STK11/LKB1, TP53, and CDKN2A/B—the latter coupled with low TTF1 expression—define three major subgroups of KRAS-mutant lung adenocarcinoma with distinct biology, patterns of immune-system engagement, and therapeutic vulnerabilities. Cancer Discov; 5(8); 860–77. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783Keywords
Other Versions
This publication has 58 references indexed in Scilit:
- MEK inhibition in non-small cell lung cancerLung Cancer, 2014
- Dragging Ras Back in the RingCancer Cell, 2014
- Targeted Therapies in Non-Small Cell Lung Cancer: Emerging Oncogene Targets Following the Success of Epidermal Growth Factor ReceptorSeminars in Oncology, 2014
- K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactionsNature, 2013
- The quest to overcome resistance to EGFR-targeted therapies in cancerNature Medicine, 2013
- Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant ChemotherapyJournal of Clinical Oncology, 2013
- ALK in Lung Cancer: Past, Present, and FutureJournal of Clinical Oncology, 2013
- Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 studyThe Lancet Oncology, 2013
- Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical OutcomeJNCI Journal of the National Cancer Institute, 2012
- A Gene Expression Signature Associated with “K-Ras Addiction” Reveals Regulators of EMT and Tumor Cell SurvivalCancer Cell, 2009