TY - JOUR
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 B.
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.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/8/1
Y1 - 2015/8/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84938794719&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938794719&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-14-1236
DO - 10.1158/2159-8290.CD-14-1236
M3 - Article
C2 - 26069186
AN - SCOPUS:84938794719
SN - 2159-8274
VL - 5
SP - 861
EP - 878
JO - Cancer discovery
JF - Cancer discovery
IS - 8
ER -