On September 9, 2026 Actuate Therapeutics, Inc. (NASDAQ: ACTU) ("Actuate" or the "Company"), a clinical-stage biopharmaceutical company, focused on developing novel therapies for high-impact, difficult-to-treat cancers, reported new preclinical data evaluating elraglusib in combination with zoldonrasib (RMC-9805), an investigational RAS(ON) G12D-selective inhibitor, and daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, in pancreatic ductal adenocarcinoma (PDAC), including models resistant to FOLFIRINOX chemotherapy. The studies were conducted in collaboration with investigators at Northwestern University and the Mayo Clinic.

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Across a panel of murine KPC pancreatic cancer cell lines, the addition of elraglusib to zoldonrasib resulted in greater inhibition of tumor-cell growth compared with zoldonrasib alone. Synergistic combination activity was also observed across human patient-derived xenograft (PDX)-derived pancreatic cancer cell lines, demonstrating the effect across multiple independent pancreatic cancer models. Studies of elraglusib in combination with daraxonrasib were also conducted, demonstrating synergistic anti-cancer activity compared with either agent alone. Together, the findings with two distinct RAS-targeted agents provide evidence that the combination effect of elraglusib extends beyond a single RAS inhibitor.

"The emergence of direct RAS inhibitors represents a major advance in pancreatic cancer and creates an opportunity to identify combinations capable of further enhancing RAS-directed activity," said Tanios "Tony" Bekaii-Saab, MD, FASCO – Chair for the Division of Hematology/Medical Oncology, Mayo Clinic in Arizona. "Importantly, the enhanced activity observed when elraglusib was combined with either zoldonrasib or daraxonrasib, two distinct RAS-targeted agents, highlights the potential for elraglusib to synergize with diverse RAS-directed therapies. Based on the unique and complementary mechanisms of action of elraglusib with these new RAS inhibition therapies, we are eager to evaluate the potential of combining elraglusib with RAS inhibition therapies in a clinical setting to expand treatment opportunities across RAS-driven diseases, including pancreatic cancer."

Separate studies evaluated the combination of elraglusib with zoldonrasib in FOLFIRINOX-resistant murine and human pancreatic cancer models. Both murine and human models demonstrated that the combination of elraglusib with zoldonrasib in vitro resulted in enhanced anti-tumor activity of the combination and greater reductions in tumor cell viability compared with either agent alone.

"Resistance to frontline chemotherapy remains a major challenge in pancreatic cancer, underscoring the need for new therapeutic strategies to be used after patients progress on FOLFIRINOX," said Dr. Deva Mahalingam, Professor of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University. "Across multiple FOLFIRINOX-resistant pancreatic cancer models, we observed greater antitumor activity when elraglusib was combined with zoldonrasib than with either agent alone, with quantitative analysis supporting enhanced anti-tumor activity and potential synergistic interactions of the combination in the models evaluated. These findings provide a compelling rationale to further investigate whether combining GSK-3β (elraglusib) and RAS G12D inhibition can enhance therapeutic activity in treatment-resistant pancreatic cancer. We look forward to participating in advancing the development of elraglusib in upcoming clinical trials, including combination trials with these most promising RAS inhibitors."

Key preclinical findings

Across murine KPC and human PDX-derived pancreatic cancer cell lines, the addition of elraglusib to zoldonrasib reduced cell growth beyond that observed with zoldonrasib alone across all models tested.
Elraglusib in combination with daraxonrasib demonstrated enhanced activity across multiple murine/human PDAC models compared with daraxonrasib alone.
In independent cell line models of FOLFIRINOX-resistant PDAC, both murine and human models of elraglusib plus zoldonrasib produced greater reductions in tumor-cell viability than either agent alone

Additional studies are ongoing, with results planned for presentation at upcoming medical conferences.

"RAS-targeted therapies are rapidly reshaping the treatment landscape for pancreatic cancer, highlighted by the recent FDA approval of daraxonrasib, the first broad RAS-targeted therapy approved for metastatic pancreatic cancer," said Daniel Schmitt, President and Chief Executive Officer of Actuate Therapeutics. "What is particularly compelling about the synergy data with elraglusib is the breadth and consistency of these findings. Elraglusib enhanced RAS-targeted activity across multiple murine and human models, with two distinct RAS inhibitors, and in models resistant to FOLFIRINOX. We believe these independent findings strengthen the potential for elraglusib to work synergistically with RAS-directed therapies and establish an important new combination approach in pancreatic and potentially other RAS-driven cancers."

(Press release, Actuate Therapeutics, SEP 9, 2026, View Source [SID1234670704])