Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models
Open accessAbstract
KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers.
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Combination treatments with navitoclax have been widely trialed in other in vivo strains and patients without major reported toxicities.
“combination treatments with navitoclax have been widely trialed in other in vivo strains and patients without major reported toxicities”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in <i>KRASG12C</i> -mutant Colorectal Cancer (2023) · cites this paper as [46]
The Results (page not available) report that mice receiving navitoclax plus selumetinib showed no overt signs of toxicity across three KRAS-mutant xenograft models. The paper does not establish that navitoclax combinations were widely trialed in other in vivo strains or in patients without major reported toxicities; it instead proposes clinical evaluation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPreclinical studies have demonstrated that knockdown or suppression of KRAS or downstream signaling in KRAS-mutant cell lines often fails to induce apoptosis.
“Preclinical studies have demonstrated that knockdown or suppression of KRAS or downstream signaling in KRAS-mutant cell lines often fails to induce apoptosis11–13.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [12]
The Discussion (page unavailable) says MEK inhibition, which suppresses a downstream KRAS pathway, is largely cytostatic and caused less than 25% apoptosis in 90% of KRAS-mutant cell lines tested. This supports the claim about downstream signaling, but the passages do not establish that KRAS knockdown itself often fails to induce apoptosis. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCombining MEK inhibitors with BH3 mimetics, which competitively bind to BCL-XL or MCL-1 and liberate BIM, can induce apoptosis and lead to regression of KRAS-mutant tumors.
“Combining MEK inhibitors with BH3 mimetics, which competitively bind to BCL-XL or MCL-1 and liberate BIM, can induce apoptosis and lead to regression of KRAS-mutant tumors12,16,17.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [12]
The Results (page not provided) report that combining the BCL-XL inhibitor ABT-263 with a MEK inhibitor induced apoptosis and tumor regressions in KRAS-mutant cancer models. The paper also reports that ABT-263 disrupted BCL-XL’s association with BIM, but explicitly says ABT-263 does not effectively inhibit MCL-1; it does not establish the claimed MCL-1-binding alternative. (LLM, conf=0.89)
Experimental — accuracy not yet measuredGenomic features associated with sensitivity to BH3 mimetics in oncogene-addicted solid tumors have been elusive.
“Our finding that LKB1 regulates the apoptotic dependency of KRAS-mutant lung cancers is unexpected, as genomic features associated with sensitivity to BH3 mimetics in oncogene-addicted solid tumors have been elusive12,16,17.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [12]
The Results (page not supplied) say that biomarkers predicting sensitivity to combined BCL-XL/MEK inhibition are needed, which supports the idea that predictors were not established. But the paper studies a BH3 mimetic combined with a MEK inhibitor in KRAS-mutant models; it does not establish that genomic predictors of BH3-mimetic sensitivity have been elusive across oncogene-addicted solid tumors. It also reports gene-expression and epithelial/mesenchymal features associated with response to the combination. (LLM, conf=0.78)
Experimental — accuracy not yet measuredBcl-xL plays an important role in regulating sensitivity to chemotherapy and other targeted therapies.
“a number of studies have shown that Bcl-xL plays an important role in regulating sensitivity to chemotherapy and other targeted therapies”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in <i>KRASG12C</i> -mutant Colorectal Cancer (2023) · cites this paper as [46]
The Results (page unavailable) show that BCL-XL knockdown increased the effect of the MEK inhibitor selumetinib in KRAS-mutant cancer cells, supporting a role in sensitivity to a targeted therapy. The paper does not establish a role in sensitivity to chemotherapy, so that part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
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Self-citation“Pathway drug cocktail”: targeting Ras signaling based on structural pathways
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“Although less well tolerated in our in vivo strain, combination treatments with navitoclax have been widely trialed in other in vivo strains and patients without major reported toxicities (46, 49).”
BackgroundWEE1 confers resistance to KRASG12C inhibitors in non-small cell lung cancer
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LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers
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“Our fi nding that LKB1 regulates the apoptotic dependency of KRAS -mutant lung cancers is unexpected, as genomic features associatedwithsensitivitytoBH3mimeticsinoncogene-addictedsolid tumorshave been elusive 12,16,17 .”
Self-citation
- Authors
- Corcoran, R. B., Cheng, K. A., Hata, A. N., Faber, A. C., Ebi, H., Coffee, E. M., Greninger, P., Brown, R. D., Godfrey, J. T., Cohoon, T. J., Song, Y., Lifshits, E., Hung, K. E., Shioda, T., Dias-Santagata, D., Singh, A., Settleman, J., Benes, C. H., Mino-Kenudson, M., Wong, K.-K., & Engelman, J. A.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Tufts Medical Center (US)
- Massachusetts General Hospital (US)
- Boston University (US)
- Genentech (US)
- Corresponding author
- Engelman, Jeffrey A.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 23
- Issue
- 1
- Pages
- 121-128
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3667614
- OpenAlex
- W2009333774
- Cited by
- 377
- References
- 36
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 17 · 2023: 21 · 2022: 15 · 2021: 31 · 2020: 23 · 2019: 34 · 2018: 30 · 2017: 38 · 2016: 37 · 2015: 44 · 2014: 41 · 2013: 31
- FWCI
- 14.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Cancer Society
- Conquer Cancer Foundation
- Damon Runyon Cancer Research Foundation
- AstraZeneca
- Massachusetts General Hospital
- National Institutes of Health (5u54hg006097-03)
- National Human Genome Research Institute (1U54HG006097-01, U54-HG006097)
- National Cancer Institute (P50CA127003, R01CA166480, U01CA141457, R01CA122794, R01CA140594, P50CA090578, K08CA120060, K99CA149169, R01CA163896, K08CA166510, UM1CA186709, R01CA137008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- KRAS-mutant cancer, BCL-XL inhibition, MEK inhibition, synthetic lethality, navitoclax, combination therapy, apoptosis, lung cancer, xenograft tumor regression, targeted cancer therapy
- MeSH terms
- Aniline Compounds, Animals, Antineoplastic Agents, Benzimidazoles, Drug Screening Assays, Antitumor, Humans, Neoplasms, Sulfonamides, Proto-Oncogene Proteins p21(ras), MAP Kinase Kinase Kinases, bcl-X Protein, Mice
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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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