Co-occurring Genomic Alterations Define Major Subsets of KRAS -Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
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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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Inactivating mutations or loss of STK11/LKB1 define one of the major genomic sub-groups of KRAS-mutant lung cancers.
“Inactivating mutations or loss of STK11/LKB1, which define one of the major genomic sub-groups of KRAS-mutant lung cancers1,19,62, are of particular interest because they are associated with decreased responsiveness to immune checkpoint blockade9,63 and poor overall prognosis64.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [19]
In KRAS-mutated NSCLC, the tumor microenvironment frequently has lack or dysfunction of tumor-infiltrating lymphocytes, especially with STK11 co-mutations.
“In KRAS-mutated NSCLC, the tumor microenvironment (TME) is frequently characterized by a lack or dysfunction of tumor-infiltrating lymphocytes (TILs), especially in the presence of co-occurring mutations in STK11 (also known as LKB1) (72, 73).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [72]
Co-mutations of tumor suppressor genes such as TP53, SMARCA4, STK11, and/or KEAP1 commonly accompany KRAS mutations.
“Concomitant mutation or deletion (hereafter, “co-mutations”) of different tumor suppressor genes (e.g., TP53, SMARCA4, STK11, and/or KEAP1) typically occur in concert with KRAS mutations (4,5).”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [5]
Combining AMG510 with anti-PD-1 or anti-PD-L1 therapy augmented T cell infiltration and achieved longer-term efficacy.
“Combining AMG510 with anti-PD-1 or anti-PD-L1 therapy augmented T cell infiltration and achieve longer-term efficacy [42, 50, 150].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [50]
In an analysis of cohorts with KRAS-mutated lung cancer that differed in clinical stage and preceding therapy, three major subgroups could be defined on the basis of RNA expression patterns and correlated with different patterns of co-occurring mutations in transformation-associated genes.
“In an analysis of cohorts with KRAS-mutated lung cancer that differed in clinical stage and preceding therapy, three major subgroups could be defined on the basis of RNA expression patterns and correlated with different patterns of co-occurring mutations in transformationassociated genes.22”
From K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways (2019) · cites this paper as [22]
There is growing evidence that KRAS-mutated lung cancer does not represent a homogeneous NSCLC subgroup.
“According to recent molecular findings, there is growing evidence that KRASmutated lung cancer does not represent a homogeneous NSCLC subgroup.15,22,39,40”
From K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways (2019) · cites this paper as [22]
KL cells exhibited heightened vulnerability to HSP90 inhibition.
“Further, KL cells exhibited heightened vulnerability to HSP90 inhibition.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
Co-occurring genomic changes profoundly affect biological behaviors, clinical outcomes, and therapeutic vulnerabilities of KRAS-mutant cancers.
“Compelling evidence showed that co-occurring genomic changes could profoundly affect biological behaviors (29–31), clinical outcomes (32), and therapeutic vulnerabilities of KRAS-mutant cancers (33, 34).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
Genomic alterations co-occurring with mutant KRAS stratify lung adenocarcinomas and define pathobiological properties and therapeutic vulnerabilities.
“This work argued that genomic alterations co-occurring with mutant KRAS stratify lung adenocarcinomas and define pathobiological properties and therapeutic vulnerabilities.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
KP tumors had higher levels of somatic mutations, inflammatory and immune checkpoint markers, and prolonged relapse-free survival.
“while higher levels of somatic mutations, inflammatory and immune checkpoint markers, and prolonged relapse-free survival were observed in KP tumors.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
KL tumors have lower expression of immune markers such as PD-L1 if KEAP1 is co-mutated.
“and KL tumors with lower expression of immune markers (e.g., PD-L1) if KEAP1 co-mutated”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
An integrative study identified three major subsets of KRAS-mutant lung adenocarcinoma defined by co-occurring genetic alterations in STK11/LKB1 (KL), TP53 (KP), and CDKN2A/B (KC).
“An integrative study of genomics, transcriptomics, and proteomics in early-stage and chemo-refractory KRAS-mutant lung adenocarcinomas identified three major subsets defined by co-occurring genetic alterations in STK11/LKB1 (KL subgroup), TP53 (KP subgroup), and CDKN2A/B (KC subgroup) (29).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
KC tumors are associated with suppressed mTORC1 signaling.
“with KC tumors associated with suppressed mTORC1 signaling”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
The three KRAS-mutant lung adenocarcinoma subgroups differ in biological properties and therapeutic vulnerabilities.
“The three subgroups differ in biological properties and therapeutic vulnerabilities”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
Co-occurring genetic mutations can lead to differential downstream effectors engaged by mutant KRAS and have been reported to significantly affect tumor immune signatures and responses to immunotherapy.
“Co-occurring genetic mutations, which can lead to differential downstream effectors engaged by mutant KRAS, have been reported to significantly affect the tumor immune signatures (25, 29, 31, 35) and responses to immunotherapy (30).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
Several preclinical studies suggested that tumors harboring KRAS mutations might be associated with a vulnerability to immunotherapies, in particular those with concomitant TP53 mutations.
“Interestingly, several preclinical studies suggested that tumors harboring KRAS mutations might be associated with a vulnerability to immunotherapies, in particular those with concomitant TP53 mutations (29, 92, 93).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [29]
TP53 mutations are under-represented among KRAS-mutant LUAD compared to other oncogene-driven subgroups, yet p53 inactivation is common and impactful in KRAS-mutant LUAD.
“For example, mutations in TP53 (which encodes p53) are under-represented among KRAS-mutant LUAD compared to other oncogene-driven subgroups, yet p53 inactivation is common and impactful in KRAS-mutant LUAD67–71.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
One subgroup (KP) was dominated by co-occurring TP53 alterations.
“one subgroup was dominated by co-occurring TP53 alterations (thereafter referred to as KP)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
A second cluster (KL) was characterized by co-mutations or genomic loss in LKB1 and was further enriched in somatic mutations in KEAP1 and ATM.
“whereas co-mutations or genomic loss in LKB1 (also known as STK11) were a hallmark of the second cluster (referred to as KL), that was further enriched in somatic mutations in KEAP1 and ATM.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
A third cluster (KC) was significantly enriched for bi-allelic inactivation of the CDKN2A/CDKN2B locus and was defined by lack of NKX2-1 expression.
“Bi-allelic inactivation of the CDKN2A/CDKN2B locus was significantly enriched in the third cluster (referred to as KC), that was defined by lack of NKX2–1 expression.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
Activating mutations in KRAS are the most prevalent oncogenic driver event in both early-stage and metastatic LUAD, occurring in 25-32% of tumors.
“Activating mutations in KRAS are the most prevalent oncogenic driver event in both early-stage and metastatic LUAD, occurring in 25–32% of tumors34, 59, 60, 62, 67.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
Distinct KRAS alleles were not differentially distributed between the three clusters, with the exception of enrichment for KRASG12D in the KC subgroup in some cohorts.
“Notably, distinct KRAS alleles were not differentially distributed between the three clusters – with the exception of enrichment for KRASG12D in the KC subgroup in some cohorts.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
Superimposition of somatic genetic alterations of key tumor suppressor genes revealed non-overlapping patterns of co-occurring genomic alterations in the three subgroups.
“Remarkably, superimposition of somatic genetic alterations of key tumor suppressor genes revealed non-overlapping patterns of co-occurring genomic alterations in the three subgroups”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
We previously identified three robust and reproducible transcriptomic sub-groups of KRAS-mutant LUAD by applying non-negative matrix factorization consensus clustering to RNASeq data from 68 tumors from TCGA.
“We previously identified three robust and reproducible transcriptomic sub-groups of KRAS-mutant LUAD by applying non-negative matrix factorization consensus clustering81–83 to RNASeq data from 68 tumors from The Cancer Genome Atlas (TCGA) dataset67.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
Somatic genomic alterations in CDKN2A and CDKN2B are observed in ~20% and ~12% of metastatic KRAS-mutant NSCLC respectively, and bi-allelic loss of the CDKN2A/CDKN2B locus is a hallmark of the KC subgroup.
“Somatic genomic alterations in CDKN2A [encoding the p16 and p14ARF (p19ARF in the mouse) tumor suppressors] and CDKN2B (encoding p15) are observed in ~20% and ~12% of metastatic KRAS-mutant NSCLC respectively and bi-allelic loss of the CDKN2A/CDKN2B locus is a hallmark of the KC subgroup15, 67.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
Selection against complete ATM inactivation may explain the mutual exclusivity of ATM and TP53 mutations in human LUAD as well as the enrichment of ATM mutations in the KL subgroup.
“Selection against complete ATM inactivation may explain the mutual exclusivity of ATM and TP53 mutations in human LUAD as well as the enrichment of ATM mutations in the KL subgroup67.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
About one quarter of KRAS-mutant LUAD carry inactivating LKB1 alterations.
“Inactivating LKB1 genomic alterations, present in ~25% of KRAS-mutant LUAD”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
Several chemically different HSP90 inhibitors also target LKB1-deficient cells.
“and to several structurally distinct inhibitors of the HSP90 family of molecular chaperones67.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [67]
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“Inactivating mutations or loss of STK11 / LKB1, which de fi ne one of the major genomic sub-groups of KRAS - mutant lung cancers 1,19,62 , are of particular interest because they are associated with decreased responsiveness to immune checkpoint blockade 9,63 and poor overall prognosis 64 .”
A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer
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- Authors
- Skoulidis, F., Byers, L. A., Diao, L., Papadimitrakopoulou, V. A., Tong, P., Izzo, J., Behrens, C., Kadara, H., Parra, E. R., Canales, J. R., Zhang, J., Giri, U., Gudikote, J., Cortez, M. A., Yang, C., Fan, Y., Peyton, M., Girard, L., Coombes, K. R., Toniatti, C., Heffernan, T. P., Choi, M., Frampton, G. M., Miller, V., Weinstein, J. N., Herbst, R. S., Wong, K.-K., Zhang, J., Sharma, P., Mills, G. B., Hong, W. K., Minna, J. D., Allison, J. P., Futreal, A., Wang, J., Wistuba, I. I., & Heymach, J. V.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- 5Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 1Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Harold C. Simmons Comprehensive Cancer Center (US)
- The Ohio State University Wexner Medical Center (US)
- Seoul National University (KR)
- Foundation Medicine (United States) (US)
- Yale Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- 4Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Corresponding author
- Heymach, John V.
- ORCID
- Skoulidis, Ferdinandos
- Byers, Lauren A.
- Diao, Lixia
- Papadimitrakopoulou, Vassiliki A.
- Behrens, Carmen
- Kadara, Humam
- Parra, Edwin R.
- Zhang, Jianjun
- Giri, Uma
- Yang, Chao
- 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 B.
- Hong, Waun K.
- Minna, John D.
- Allison, James P.
- Wang, Jing
- Wistuba, Ignacio I.
- Heymach, John V.
- Venue
- Cancer Discovery
- Published
- 2015-08-01
- Volume
- 5
- Issue
- 8
- Pages
- 860-877
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4527963
- OpenAlex
- W2145411470
- Cited by
- 936
- References
- 59
- Citations by year
- 2026: 82 · 2025: 90 · 2024: 87 · 2023: 86 · 2022: 114 · 2021: 123 · 2020: 88 · 2019: 72 · 2018: 70 · 2017: 55 · 2016: 52 · 2015: 10 · 2014: 1
- FWCI
- 49.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ca205150-04)
- National Cancer Institute (R01-CA205150, R01CA166480, CA 016672, P50CA098258, T32CA009666, R01CA140594, R01CA155196, P50CA070907, P01CA154303, R01CA168484, R01CA163896, P01CA120964, P30CA016672)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- KRAS-mutant lung adenocarcinoma, tumor subtypes, STK11/LKB1, TP53, mTORC1 signaling, tumor immune microenvironment, PD-L1, drug sensitivity, Hsp90 inhibitors, mucinous histology, relapse-free survival
- MeSH terms
- Adenocarcinoma of Lung, AMP-Activated Protein Kinase Kinases, Adenocarcinoma, DNA-Binding Proteins, Humans, Inflammation, Lung Neoplasms, Mutation, Prognosis, Transcription Factors, Genetic Variation, Signal Transduction, Gene Expression, Cluster Analysis, Protein Serine-Threonine Kinases, Oxidative Stress, ras Proteins, Gene Expression Profiling, Genomics, Tumor Suppressor Proteins, Cell Line, Tumor, AMP-Activated Protein Kinases
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