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Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer
Open accessPublished version of a preprint
Abstract
Abstract High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including BCL2L1 (BCL-XL) and BCL2L2 (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of BCL2L1 decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. Implications: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.
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“Results agree with previous CRISPR-Cas9 screens, underscoring the role of apoptotic regulatory genes in modifying sensitivity to cancer therapy.”
From Integrated drug profiling and CRISPR screening identify BCR::ABL1-independent vulnerabilities in chronic myeloid leukemia (2024) · cites this paper as [35]
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BCL-W is a regulator of microtubule inhibitor-induced mitotic cell death
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“Additionally, greater expression of antiapoptotic proteins BCL2L1 and MCL1 is associated with worse survival outcomes in patients with ovarian cancer [29].”
BackgroundSelf-citationBCL-w: apoptotic and non-apoptotic role in health and disease
Hartman, M. L., & Czyż, M. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2417-0 · Cited by 107
Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics
Montero, J., & Haq, R. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1334 · Cited by 75
“Combining several BH3 mimetics, such as MCL1 and BCL2/BCLXL inhibitors, has had significant efficacy in preclinical in vitro and in vivo models (70, 130), leading to their current evaluation in clinical trials (e.”
BackgroundSelf-citation
Metadata
- Authors
- Stover, E. H., Baco, M. B., Cohen, O., Li, Y. Y., Christie, E. L., Bagul, M., Goodale, A., Lee, Y., Pantel, S., Rees, M. G., Wei, G., Presser, A. G., Gelbard, M. K., Zhang, W., Zervantonakis, I. K., Bhola, P. D., Ryan, J., Guerriero, J. L., Montero, J., Liang, F. J., Cherniack, A. D., Piccioni, F., Matulonis, U. A., Bowtell, D. D. L., Sarosiek, K. A., Letai, A., Garraway, L. A., Johannessen, C. M., & Meyerson, M.
- Affiliations
- Broad Institute (US)
- The University of Melbourne (AU)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Meyerson, Matthew
- ORCID
- Stover, Elizabeth H.
- Cohen, Ofir
- Li, Yvonne Y.
- Christie, Elizabeth L.
- Goodale, Amy
- Lee, Yenarae
- Rees, Matthew G.
- Presser, Adam G.
- Gelbard, Maya K.
- Zervantonakis, Ioannis K.
- Bhola, Patrick D.
- Ryan, Jeremy
- Guerriero, Jennifer L.
- Montero, Joan
- Liang, Felice J.
- Cherniack, Andrew D.
- Piccioni, Federica
- Matulonis, Ursula A.
- Bowtell, David D.L.
- Sarosiek, Kristopher A.
- Letai, Anthony
- Garraway, Levi A.
- Johannessen, Cory M.
- Meyerson, Matthew
- Venue
- Molecular Cancer Research
- Published
- 2019-11-01
- Volume
- 17
- Issue
- 11
- Pages
- 2281-2293
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC6825578
- OpenAlex
- W2970182852
- Cited by
- 49
- References
- 50
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 10 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 7
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Victorian Cancer Agency (ECSG15012)
- National Health and Medical Research Council (APP1124309, APP1092856)
- SU2C TVF (D2015-037)
- Ministerio de Economia y Competitividad (RYC-2015-18357)
- Postdoctoral Individual National Research Service (F32CA180733)
- NCI (K99CA222554, 1U54CA224068, 1R01CA219943, 1R35CA197568)
- NHMRC (APP1117044)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- high-grade serous ovarian cancer, chemoresistance, anti-apoptotic genes, Bcl-xL, Bcl-w, Bcl-2, Mcl-1, apoptosis, cisplatin, paclitaxel, Bcl-xL inhibitors, olaparib, CRISPR-Cas9 knockout screen, drug resistance
- MeSH terms
- Antineoplastic Agents, Cisplatin, Female, Humans, Ovarian Neoplasms, Apoptosis, Paclitaxel, Drug Resistance, Neoplasm, Genomics, Cell Line, Tumor, Apoptosis Regulatory Proteins, bcl-X Protein, Myeloid Cell Leukemia Sequence 1 Protein
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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