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Updated: May 23, 2025
Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical
Margo I Orlen1,2, William P Vostrejs1,2, Rina Sor2
1Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract:
Activating mutations in KRAS drive tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), promoting tumor cell proliferation and contributing to an immunosuppressive tumor microenvironment, rendering PDAC tumors insensitive to immunotherapy. RAS(ON) multi-selective inhibitors, such as daraxonrasib (RMC-6236) and RMC-7977, target the active state of RAS, with potent antitumor activity in PDAC murine models. In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment. The depth and duration of tumor regression depended on T cells and conventional dendritic cells. Moreover, the combination of RAS(ON) multi-selective inhibitors with immunotherapy conferred deeper and more durable tumor regressions, including complete responses not seen with either treatment alone. In summary, concurrent inhibition of mutant and wild-type RAS is active in concert with T-cell immunotherapy, revealing RAS(ON) multi-selective inhibitors as a potential therapeutic immuno-sensitizing strategy in PDAC.
Significance:
RAS(ON) multi-selective inhibitors enhance antitumor immunity in preclinical models of PDAC, resulting in deeper and more durable responses when combined with immunotherapy. These findings support the clinical evaluation of immune-based strategies that may prolong the response to RAS inhibitor therapies as well as overcome issues of therapeutic resistance to inhibitors alone. See related commentary by Lasse Opsahl and Pasca di Magliano, p. 1537.
Insights
RAS(ON) multi-selective inhibitors rapidly shrink pancreatic ductal adenocarcinoma (PDAC) tumors in mice. Combining these inhibitors with immunotherapy enhances anti-tumor effects, suggesting a new strategy for PDAC treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Activating KRAS mutations fuel pancreatic ductal adenocarcinoma (PDAC) growth and create an immunosuppressive tumor microenvironment (TME), hindering immunotherapy effectiveness.
- RAS(ON) multi-selective inhibitors target the active form of RAS, demonstrating anti-tumor potential in preclinical PDAC models.
Purpose of the Study:
- To investigate the efficacy of RAS(ON) multi-selective inhibitors in PDAC.
- To evaluate the impact of these inhibitors on the tumor microenvironment (TME).
- To assess the combination therapy of RAS(ON) inhibitors with immunotherapy in PDAC.
Main Methods:
- Treatment of PDAC murine models with RAS(ON) multi-selective inhibitors.
- Analysis of immune cell populations within the tumor microenvironment (TME).
- Evaluation of combination therapy with immunotherapy.
Main Results:
- RAS(ON) multi-selective inhibition induced rapid and significant PDAC tumor regressions in immunocompetent mice.
- Inhibition modulated the TME by decreasing myeloid cells and increasing T cells and macrophages.
- Tumor regression depth and duration were dependent on T cells and conventional dendritic cells.
- Combination therapy resulted in deeper, more durable regressions, including complete responses.
Conclusions:
- RAS(ON) multi-selective inhibitors demonstrate potent anti-tumor activity in PDAC.
- These inhibitors remodel the TME, enhancing immune cell infiltration.
- Combination with immunotherapy offers a promising strategy for overcoming PDAC resistance and improving therapeutic outcomes.
