Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities

Cancer Discovery - Tập 5 Số 8 - Trang 860-877 - 2015
Ferdinandos Skoulidis1, Lauren A. Byers1, Lixia Diao2, Vassiliki A. Papadimitrakopoulou1, Pan Tong2, Julie Izzo3, Carmen Behrens1, Humam Kadara3, Edwin R. Parra3, Jaime Rodriguez Canales3, Jianjun Zhang4, Uma Giri1, Jayanthi Gudikote1, María Angélica Cortez5, Chao Yang1, You Hong Fan1, Michael Peyton6, Luc Girard6, Kevin R. Coombes7, Carlo Toniatti8, Timothy P. Heffernan8, Murim Choi9, Garrett M. Frampton10, Vincent A. Miller10, John N. Weinstein2, Roy S. Herbst11, Kwok‐Kin Wong12, Jianhua Zhang8, Padmanee Sharma13, Gordon B. Mills14, Waun Ki Hong15, John D. Minna6, James P. Allison16, P. Andrew Futreal4, Jing Wang2, Ignacio I. Wistuba3, John V. Heymach1
11Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
22Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
33Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
44Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
55Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
66Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
77Department of Biomedical Informatics, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
88Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
99Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
1010Foundation Medicine, Cambridge, Massachusetts.
1111Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, New Haven, Connecticut.
1212Department of Medical Oncology and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
1313Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1414Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1515Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1616Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Tóm tắt

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. 783

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Cancer Discovery

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