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.
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.
Authors
Schulz Schulz, Leitner Leitner, Rabierad Rabierad, Khan Khan, Ehlers Ehlers, Escobar Escobar, Jaster Jaster, Vollmar Vollmar, Zechner Zechner
View on Pubmed