title: Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ferdinandos
authors.initials: F
authors.lastname: Skoulidis
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Papadimitrakopoulou
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pan
authors.initials: P
authors.lastname: Tong
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Julie
authors.initials: J
authors.lastname: Izzo
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Parra
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaime Rodriguez
authors.initials: JR
authors.lastname: Canales
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Uma
authors.initials: U
authors.lastname: Giri
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Gudikote
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cortez
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.affiliation: Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Department of Biomedical Informatics, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.affiliation: Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, New Haven, Connecticut.
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.affiliation: Department of Medical Oncology and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Waun K
authors.initials: WK
authors.lastname: Hong
authors.affiliation: Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Andrew
authors.initials: A
authors.lastname: Futreal
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jheymach@mdanderson.org.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D014644:Genetic Variation; D023281:Genomics / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D009154:Mutation; D018384:Oxidative Stress; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D018631:ras Proteins