Benefits and challenges of adding BKM120 to a BI-3406 plus trametinib combination therapy

Achieving a balance between efficacy and side effects is essential for the success of new combinatorial cancer therapies. This study investigated the impact of adding BKM120, a PI3K inhibitor, to a dual regimen consisting of BI-3406, a KRAS/SOS1 inhibitor, and trametinib, a MEK inhibitor.

The therapeutic effects of these drug combinations were evaluated in the pancreatic cancer cell line 6606PDA using both monolayer and three-dimensional cultures. Additionally, their efficacy and potential side effects were assessed in vivo using a syngeneic orthotopic mouse model of pancreatic cancer.

In vitro studies demonstrated that the addition of BKM120 to BI-3406 and trametinib significantly reduced cell viability in both monolayer and three-dimensional cultures. However, in a syngeneic pancreatic cancer mouse model, the triple therapy failed to significantly improve survival outcome compared to the dual therapy. Tumor weights were unaffected in female mice, while a minor, non-significant reduction was observed in male mice. This was accompanied by a slight, non-significant decrease in cancer cell proliferation. In the triple therapy group, Cdkn2a expression in tumors, a marker for senescence, remained largely unchanged. However, PD-L1 was significantly reduced in males, and CD8⁺ T-cell infiltration was notably enhanced in females. Importantly, the triple therapy demonstrated several concerning drawbacks. It significantly increased lung metastases in female mice, reduced lymphocyte and erythrocyte counts, and elevated C-peptide concentrations in both sexes. Furthermore, behavioral analysis indicated a significant decline in burrowing and nesting activities among female mice during specific experimental phases.

The addition of BKM120 to the combination of BI-3406 and trametinib provides minimal therapeutic benefit while introducing significant adverse effects, underscoring the need for caution when considering clinical applications.