Partial FAK suppression promotes tumor growth, an effect reversed by macrophage p110δ PI3K inactivation

FAK/PTK2 is widely considered a therapeutic target in cancer, although its role in tumorigenesis remains context-dependent. Here, we investigated whether different degrees of FAK suppression produce distinct effects on tumor progression and whether macrophage p110δ PI3K inactivation can counteract adverse effects associated with incomplete FAK inhibition. Using MDA-MB-231 breast cancer cell clones stably transfected with FAK/PTK2-shRNA, we found that strong FAK suppression impaired tumor growth, whereas moderate FAK silencing promoted rapid tumor expansion in female and male mice. Intratumoral FAK/PTK2-siRNA inducing moderate FAK suppression similarly accelerated breast tumor growth, increased proliferation, reduced apoptosis, and increased circulating tumor cells. Transfer of macrophages expressing genetically inactive p110δ significantly reduced the tumor burden induced by moderately FAK-silenced breast cancer cells, decreased proliferation, and increased apoptosis. In melanoma tumors, suboptimal pharmacological inhibition of FAK increased tumor burden, whereas combined treatment with a selective p110δ inhibitor prevented this effect, reduced circulating melanoma cells, suppressed proliferation, and enhanced apoptosis. Since FAK inhibitors may not achieve complete and sustained inhibition of FAK activity in vivo, our findings highlight the possibility that partial FAK suppression may generate adverse biological outcomes and identify macrophage p110δPI3K as a complementary therapeutic strategy to prevent tumor-promoting consequences arising from incomplete FAK inhibition.