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Cancer Discov. 2015 Aug;5(8):860-77. doi: 10.1158/2159-8290.CD-14-1236. Epub 2015 Jun 11.

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

Author information

1
Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
7
Department of Biomedical Informatics, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
8
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
10
Foundation Medicine, Cambridge, Massachusetts.
11
Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, New Haven, Connecticut.
12
Department of Medical Oncology and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
13
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
14
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
15
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
16
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
17
Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jheymach@mdanderson.org.

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.

PMID:
26069186
PMCID:
PMC4527963
DOI:
10.1158/2159-8290.CD-14-1236
[Indexed for MEDLINE]
Free PMC Article

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