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Background <p>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.</p> Methods <p>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.</p> Results <p><i>In vitro</i> 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, <i>Cdkn2a</i> expression in tumors, a marker for senescence, remained largely unchanged. However, PD-L1 was significantly reduced in males, and CD8<sup>+</sup> T-cell infiltration was notably enhanced in females. Importantly, the triple therapy demonstrated several concerning drawbacks.</p> <p>It significantly increased lung metastases in female mice, reduced lymphocyte and erythrocyte counts, and elevated C-peptide concentrations in both sexes.</p> <p>Furthermore, behavioral analysis indicated a significant decline in burrowing and nesting activities among female mice during specific experimental phases.</p> Conclusion <p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月3日

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  • Benjamin Schulz,
  • Emily Leitner,
  • Mehrdad Rabierad,
  • Muhammad Imran Khan,
  • Luise Ehlers,
  • Hugo Murua Escobar,
  • Robert Jaster,
  • Brigitte Vollmar,
  • Dietmar Zechner

摘要

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Graphical Abstract