Researchers at The University of Texas MD Anderson Cancer Center have uncovered a functional role for KRAS mutations in pancreatic cancer and rapidly translated these findings into a novel therapeutic approach combining a KRAS G12D inhibitor with immune checkpoint inhibitors for early- and late-stage KRAS G12D-mutant pancreatic cancer.
Reviewed by Lily Ramsey, LLMAug 24 2023 The combination therapy led to durable tumor elimination and significantly improved survival outcomes in preclinical models, leading to the launch of a Phase I clinical trial.
"By extensively testing the functional role of KRAS, we gained important insights into how better to prime the tumor microenvironment in advanced pancreatic cancer to improve treatment responses," Kalluri said. "These results are a testament to the value of team science and to the incredible research environment at MD Anderson, which enables the accelerated and seamless translation from genetic models to clinical application.
In the Developmental Cell study, researchers examined the functional role of KRAS by generating mouse models with various genetic alterations known to accompany KRAS mutations. Genetic suppression of KRAS in these models activated the Fas pathway, which is required for cancer cell death, and resulted in a greater number of T cells and fewer myeloid cells in the tumors.
KRAS G12D inhibition depends on immune cell activation for improved, sustained treatment response in early- and late-stage tumors. Further analysis showed that the elimination of established tumors was dependent upon the activation of CD8+ T cells. If CD8+ T cells were suppressed, the tumors progressed despite treatment with MRTX1133. Following this, the researchers found that combining various immune checkpoint inhibitors with MRTX1133 led to sustained tumor regression, enhanced cancer cell clearance and improved survival outcomes.
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Combining immunotherapy with KRAS inhibitor eliminates advanced KRAS-mutant pancreatic cancer in preclinical modelsResearchers at The University of Texas MD Anderson Cancer Center have uncovered a functional role for KRAS mutations in pancreatic cancer and rapidly translated these findings into a novel therapeutic approach combining a KRAS G12D inhibitor with immune checkpoint inhibitors for early- and late-stage KRAS G12D-mutant pancreatic cancer. The combination therapy led to durable tumor elimination and significantly improved survival outcomes in preclinical models, leading to the launch of a Phase I clinical trial.
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