Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer
Open accessAbstract
Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.
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In vitro, KEAP1 co-mutations correlate with resistance to several inhibitors targeting the RTK-MAPK pathway.
“KEAP1 co-mutations are associated with resistance to multiple inhibitors of oncogenic kinases within the receptor tyrosine kinase–MAPK pathway in vitro166”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [166]
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- Authors
- McMillan, E. A., Ryu, M.-J., Diep, C. H., Mendiratta, S., Clemenceau, J. R., Vaden, R. M., Kim, J.-H., Motoyaji, T., Covington, K. R., Peyton, M., Huffman, K., Wu, X., Girard, L., Sung, Y., Chen, P.-H., Mallipeddi, P. L., Lee, J. Y., Hanson, J., Voruganti, S., Yu, Y., Park, S., Sudderth, J., DeSevo, C., Muzny, D. M., Doddapaneni, H., Gazdar, A., Gibbs, R. A., Hwang, T.-H., Heymach, J. V., Wistuba, I., Coombes, K. R., Williams, N. S., Wheeler, D. A., MacMillan, J. B., Deberardinis, R. J., Roth, M. G., Posner, B. A., Minna, J. D., Kim, H. S., & White, M. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Yonsei University (KR)
- Takeda (Japan) (JP)
- Baylor College of Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- The Ohio State University (US)
- Corresponding author
- Minna, John D.
- Kim, Hyun Seok
- White, Michael A.
- ORCID
- McMillan, Elizabeth A.
- Diep, Caroline H.
- Mendiratta, Saurabh
- Clemenceau, Jean R.
- Vaden, Rachel M.
- Covington, Kyle R.
- Peyton, Michael
- Wu, Xiaofeng
- Girard, Luc
- Mallipeddi, Prema L.
- Lee, Joo Young
- Park, Sunho
- Sudderth, Jessica
- Muzny, Donna M.
- Doddapaneni, HarshaVardhan
- Gazdar, Adi
- Gibbs, Richard A.
- Heymach, John V.
- Wistuba, Ignacio
- Coombes, Kevin R.
- Williams, Noelle S.
- Wheeler, David A.
- MacMillan, John B.
- Deberardinis, Ralph J.
- Roth, Michael G.
- Posner, Bruce A.
- Minna, John D.
- Kim, Hyun Seok
- White, Michael A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 173
- Issue
- 4
- Pages
- 864-878.e29
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5935540
- OpenAlex
- W2801384315
- Cited by
- 141
- References
- 37
- Citations by year
- 2026: 5 · 2025: 21 · 2024: 21 · 2023: 20 · 2022: 17 · 2021: 16 · 2020: 22 · 2019: 11 · 2018: 8
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (CA197717, CA176284, CA70907, CA142543, 5T32GM8203-27, 5T32CA124334-09)
- CPRIT (RP120732, RP110708, RP140110)
- Robert Welch Foundation (I-1414)
- Korea Health Technology R & D
- Korea Health Industry Development Institute (HI14C1324)
- National R&D Program for Cancer Control (1420100)
- Ministry of Health & Welfare, Republic of Korea
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- 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
- Keywords
- lung cancer, personalized treatment, somatic mutations, TTC21B, GLUT8, serine biosynthesis, cell model, patient selection
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Cytochrome P450 Family 4, Carcinoma, Non-Small-Cell Lung, Glucocorticoids, Humans, Lung Neoplasms, Microtubule-Associated Proteins, Mutation, Receptors, Glucocorticoid, Proto-Oncogene Proteins p21(ras), RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Glucose Transport Proteins, Facilitative, NF-E2-Related Factor 2, Receptor, Notch2, Small Molecule Libraries, Drug Discovery, G1 Phase Cell Cycle Checkpoints
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