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

Ferdinandos Skoulidis, Lauren A. Byers, Lixia Diao, Vassiliki A. Papadimitrakopoulou, Pan Tong, Julie Izzo, Carmen Behrens, Humam Kadara, Edwin R. Parra, Jaime Rodriguez Canales, Jianjun Zhang, Uma Giri, Jayanthi Gudikote, Maria A. Cortez, Chao Yang, Youhong Fan, Michael Peyton, Luc Girard, Kevin R. Coombes, Carlo ToniattiTimothy P. Heffernan, Murim Choi, Garrett M. Frampton, Vincent Miller, John N. Weinstein, Roy S. Herbst, Kwok Kin Wong, Jianhua Zhang, Padmanee Sharma, Gordon Mills, Waun K. Hong, John D. Minna, James P. Allison, Andrew Futrea, Jing Wang, Ignacio I. Wistuba, John V. Heymach

Research output: Contribution to journalArticle

230 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)861-878
Number of pages18
JournalCancer Discovery
Volume5
Issue number8
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Biomarkers
Therapeutics
Neoplasms
Proteomics
Immune System
Histology
Transcription Factors
Adenocarcinoma of lung
Recurrence
Mutation
Pharmaceutical Preparations
mechanistic target of rapamycin complex 1

ASJC Scopus subject areas

  • Oncology

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Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. / Skoulidis, Ferdinandos; Byers, Lauren A.; Diao, Lixia; Papadimitrakopoulou, Vassiliki A.; Tong, Pan; Izzo, Julie; Behrens, Carmen; Kadara, Humam; Parra, Edwin R.; Canales, Jaime Rodriguez; Zhang, Jianjun; Giri, Uma; Gudikote, Jayanthi; Cortez, Maria A.; Yang, Chao; Fan, Youhong; Peyton, Michael; Girard, Luc; Coombes, Kevin R.; Toniatti, Carlo; Heffernan, Timothy P.; Choi, Murim; Frampton, Garrett M.; Miller, Vincent; Weinstein, John N.; Herbst, Roy S.; Wong, Kwok Kin; Zhang, Jianhua; Sharma, Padmanee; Mills, Gordon; Hong, Waun K.; Minna, John D.; Allison, James P.; Futrea, Andrew; Wang, Jing; Wistuba, Ignacio I.; Heymach, John V.

In: Cancer Discovery, Vol. 5, No. 8, 01.01.2015, p. 861-878.

Research output: Contribution to journalArticle

Skoulidis, F, Byers, LA, Diao, L, Papadimitrakopoulou, VA, Tong, P, Izzo, J, Behrens, C, Kadara, H, Parra, ER, Canales, JR, Zhang, J, Giri, U, Gudikote, J, Cortez, MA, Yang, C, Fan, Y, Peyton, M, Girard, L, Coombes, KR, Toniatti, C, Heffernan, TP, Choi, M, Frampton, GM, Miller, V, Weinstein, JN, Herbst, RS, Wong, KK, Zhang, J, Sharma, P, Mills, G, Hong, WK, Minna, JD, Allison, JP, Futrea, A, Wang, J, Wistuba, II & Heymach, JV 2015, 'Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities', Cancer Discovery, vol. 5, no. 8, pp. 861-878. https://doi.org/10.1158/2159-8290.CD-14-1236
Skoulidis, Ferdinandos ; Byers, Lauren A. ; Diao, Lixia ; Papadimitrakopoulou, Vassiliki A. ; Tong, Pan ; Izzo, Julie ; Behrens, Carmen ; Kadara, Humam ; Parra, Edwin R. ; Canales, Jaime Rodriguez ; Zhang, Jianjun ; Giri, Uma ; Gudikote, Jayanthi ; Cortez, Maria A. ; Yang, Chao ; Fan, Youhong ; Peyton, Michael ; Girard, Luc ; Coombes, Kevin R. ; Toniatti, Carlo ; Heffernan, Timothy P. ; Choi, Murim ; Frampton, Garrett M. ; Miller, Vincent ; Weinstein, John N. ; Herbst, Roy S. ; Wong, Kwok Kin ; Zhang, Jianhua ; Sharma, Padmanee ; Mills, Gordon ; Hong, Waun K. ; Minna, John D. ; Allison, James P. ; Futrea, Andrew ; Wang, Jing ; Wistuba, Ignacio I. ; Heymach, John V. / Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. In: Cancer Discovery. 2015 ; Vol. 5, No. 8. pp. 861-878.
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T1 - Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities

AU - Skoulidis, Ferdinandos

AU - Byers, Lauren A.

AU - Diao, Lixia

AU - Papadimitrakopoulou, Vassiliki A.

AU - Tong, Pan

AU - Izzo, Julie

AU - Behrens, Carmen

AU - Kadara, Humam

AU - Parra, Edwin R.

AU - Canales, Jaime Rodriguez

AU - Zhang, Jianjun

AU - Giri, Uma

AU - Gudikote, Jayanthi

AU - Cortez, Maria A.

AU - Yang, Chao

AU - Fan, Youhong

AU - Peyton, Michael

AU - Girard, Luc

AU - Coombes, Kevin R.

AU - Toniatti, Carlo

AU - Heffernan, Timothy P.

AU - Choi, Murim

AU - Frampton, Garrett M.

AU - Miller, Vincent

AU - Weinstein, John N.

AU - Herbst, Roy S.

AU - Wong, Kwok Kin

AU - Zhang, Jianhua

AU - Sharma, Padmanee

AU - Mills, Gordon

AU - Hong, Waun K.

AU - Minna, John D.

AU - Allison, James P.

AU - Futrea, Andrew

AU - Wang, Jing

AU - Wistuba, Ignacio I.

AU - Heymach, John V.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

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