Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRAS G12D Inhibitor MRTX1133 in Pancreatic Cancer
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Abstract
MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in patients with PDAC. Significance: The combination of MRTX1133 and the FDA-approved drug venetoclax promotes cancer cell death and tumor regression in pancreatic ductal adenocarcinoma, providing rationale for testing venetoclax with KRASG12D inhibitors in patients with pancreatic cancer.
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Bcl-2 inhibition with venetoclax resensitized resistant PDAC cells to MRTX1133.
“resensitized resistant PDAC cells to MRTX1133 [160].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [160]
Bcl-2 inhibition with venetoclax significantly increased the efficacy of MRTX1133 in KRAS G12D PDAC.
“Bcl-2 inhibition with venetoclax significantly increased the efficacy of MRTX1133 in KRAS G12D PDAC”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [160]
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- [34]Kumarasamy V, Wang J, Frangou C, Wan Y, Dynka A, Rosenheck H, The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer. Cancer Res. 2024; 84(7): 1115– 32. 38294344 PMC10982648
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Differential Response and Resistance to KRAS-Targeted Therapy
Liu, Z., Lenz, H., Yu, J., & Zhang, L. (2025) · Molecular Carcinogenesis · doi:10.1002/mc.23908 · Cited by 7 · see citing works
“Bcl ‐ 2 inhibition with venetoclax significantly increased the efficacy of MRTX1133 in KRAS G12D PDAC and resensitized resistant PDAC cells to MRTX1133 [163].”
- Authors
- Becker, J. H., Metropulos, A. E., Spaulding, C., Marinelarena, A. M., Shields, M. A., Principe, D. R., Pham, T. D., & Munshi, H. G.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Munshi, Hidayatullah G.
- ORCID
- Venue
- Cancer Research
- Published
- 2024-08-13
- Volume
- 84
- Issue
- 21
- Pages
- 3629-3639
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC11532783
- OpenAlex
- W4401533489
- Cited by
- 17
- References
- 49
- Citations by year
- 2026: 8 · 2025: 9
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA265997, T32CA268935)
- U.S. Department of Veterans Affairs (I01BX005595)
- American Cancer Society (IRG-21-144-270)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- venetoclax, MRTX1133, KRAS G12D inhibitors, pancreatic ductal adenocarcinoma, BCL-2 inhibition, building information modeling, apoptosis, combination therapy, drug resistance
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Drug Synergism, Female, Heterocyclic Compounds, 2-Ring, Humans, Naphthalenes, Pancreatic Neoplasms, Sulfonamides, Proto-Oncogene Proteins p21(ras), Apoptosis, Drug Resistance, Neoplasm, Bridged Bicyclo Compounds, Heterocyclic, Proto-Oncogene Proteins c-bcl-2, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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