ArticleCancers2026
The Combination of a BCL-xL PROTAC and an mTOR Inhibitor Sensitizes Pancreatic Ductal Adenocarcinoma to KRAS
Article in Cancers, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
2 citing papers in PubMed.
- Dual targeting of BCL-XL and MCL-1 exposes a rapid and exploitable apoptotic vulnerability in non-small cell lung cancer.Cell death and differentiation · 2026Article
- Bracing for the storm: emerging resistance mechanisms to KRAS inhibitors in pancreatic cancer and strategies to overcome them.Cancer drug resistance (Alhambra, Calif.) · 2026Review
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Authors and funding
9 authors.
Funding
Abstract
BACKGROUND/
objectivesPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a five-year survival rate of approximately 13%, partly because of limited treatment options and resistance to therapies. Although the recently discovered KRAS G12D inhibitor MRTX1133 has shown promising efficacy in preclinical models, its clinical efficacy as a single agent is expected to be limited, as is the case with KRAS G12C inhibitors. Therefore, in this study, we evaluated potential combination strategies to enhance the therapeutic effect of MRTX1133. We combined MRTX1133 with the BCL-xL proteolysis-targeting chimera (PROTAC) DT2216 and the mTOR inhibitor everolimus.
methodsThe sensitization of MRTX1133 by the combination of DT2216 + everolimus was tested in KRAS G12D-mutant PDAC cell lines using colony formation and apoptosis assays. The effects of MRTX1133 and/or DT2216 + everolimus on KRAS signaling and BCL-2 family proteins were assessed by immunoblotting and/or RT-PCR. The functional roles of BIM/NOXA were elucidated via immunoprecipitation (IP) and siRNA knockdown. Triple combination efficacy was evaluated in AsPC1 parental and MRTX1133-resistant xenografts, with pharmacodynamic effects confirmed by immunoblotting and immunohistochemistry.
resultsThe triple combination leads to significantly greater colony growth inhibition and apoptosis induction as compared with single agents or two-drug combinations in multiple KRAS G12D-mutant PDAC cell lines. Mechanistically, MRTX1133 treatment increased BIM and decreased NOXA levels, and the combination of DT2216/everolimus simultaneously enhanced BIM release and stabilized NOXA. In vivo, DT2216/everolimus combination significantly potentiated the anti-tumor activity of MRTX1133 in the AsPC1 PDAC xenograft model. Furthermore, the triple combination effectively overcame acquired MRTX1133 resistance in vitro and in the AsPC1 xenograft model.
conclusionsCollectively, our findings suggest that the combination of DT2216/everolimus potentiates the anti-tumor efficacy of MRTX1133 associated with enhanced apoptosis induction and inhibition of compensatory survival signaling.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.