Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer
Open accessAbstract
Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.
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Studies connect LKB1 loss to greater sensitivity to energy stress caused by metformin or phenformin.
“Other studies have linked LKB1 loss with enhanced sensitivity to energetic stress triggered by the biguanides metformin and phenformin156”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [156]
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References 84 · Cited by 172
- Authors
- Kim, H. S., Mendiratta, S., Kim, J., Pecot, C. V., Larsen, J. E., Zubovych, I., Seo, B. Y., Kim, J., Eskiocak, B., Chung, H., McMillan, E., Wu, S., De Brabander, J., Komurov, K., Toombs, J. E., Wei, S., Peyton, M., Williams, N., Gazdar, A. F., Posner, B. A., Brekken, R. A., Sood, A. K., Deberardinis, R. J., Roth, M. G., Minna, J. D., & White, M. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Children's Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- White, Michael A.
- ORCID
- Kim, Hyun Seok
- Mendiratta, Saurabh
- Kim, Jiyeon
- Pecot, Chad Victor
- Larsen, Jill E.
- Kim, Jimi
- Chung, Hannah
- McMillan, Elizabeth
- Wu, Sherry
- Komurov, Kakajan
- Toombs, Jason E.
- Wei, Shuguang
- Peyton, Michael
- Williams, Noelle
- Gazdar, Adi F.
- Posner, Bruce A.
- Brekken, Rolf A.
- Sood, Anil K.
- Deberardinis, Ralph J.
- Roth, Michael G.
- Minna, John D.
- White, Michael A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 155
- Issue
- 3
- Pages
- 552-566
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3836195
- OpenAlex
- W2163357890
- Cited by
- 172
- References
- 84
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 6 · 2023: 13 · 2022: 7 · 2021: 16 · 2020: 15 · 2019: 16 · 2018: 9 · 2017: 19 · 2016: 17 · 2015: 29 · 2014: 14
- FWCI
- 16.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Welch Foundation
- Collins Foundation
- National Institutes of Health
- National Cancer Institute (CA148225, R01CA129451, U54CA151668, CA 70907, CA 71443, T32CA009666, R01CA071443, P50CA070907, U01CA176284, R01CA157996, CA176284, CA129451, RC2CA148225, P30CA016672, P30CA142543)
- National Center for Research Resources (S10RR027805)
- 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
- non-small cell lung cancer, molecular vulnerabilities, NLRP3 inflammasome, KRAS mutation, LKB1 mutation, COPI, gene expression signatures, tumor evolution, lung adenocarcinoma cell lines
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carcinoma, Non-Small-Cell Lung, Carrier Proteins, Drug Screening Assays, Antitumor, Female, Humans, Indoles, Lung Neoplasms, Lysosomes, Neoplasm Transplantation, Oxidative Phosphorylation, Genes, ras, Triazines, Coatomer Protein, Cell Line, Tumor, Mice, CASP8 and FADD-Like Apoptosis Regulating Protein, Molecular Targeted Therapy, Heterografts
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