Cotargeting BET proteins overcomes resistance arising from PI3K/mTOR blockade‐induced protumorigenic senescence in colorectal cancer.

Therapeutics targeting the phosphatidylinositol 3‐kinase/mammalian target of rapamycin (PI3K/mTOR) pathway initially produce potent antitumor effects, but resistance frequently occurs. Using a phosphoproteome analysis, we found that colorectal cancer (CRC) cells exhibit resistance against PI3K/mTOR inhibition through feedback activation of multiple receptor tyrosine kinases, and their downstream focal adhesion kinase, Src and extracellular signal‐regulated kinases signaling. Unexpectedly, PI3K/mTOR blockade causes senescence, mediated by the activation of the stress kinase p38. The senescent cancer cells induce the secretion of various cytokines and this senescence‐associated secretome increases migration and invasion capabilities of CRC cells. We found that cotargeting PI3K/mTOR and bromodomain and extra‐terminal domain can suppress activation of many oncogenic kinases involved in resistance to the PI3K/mTOR inhibition, induce cell death in vitro and tumor regression in vivo, and further prolong the survival of xenograft models. Our findings provide a rationale for a novel therapeutic strategy to overcome resistance to the PI3K/mTOR inhibitors in CRC. What's new? Cancer therapeutics targeting the PI3K/mTOR pathway initially produce potent anti‐tumor effects, but resistance frequently occurs. Here, the authors carried out a phosphoproteome analysis to investigate the resistance mechanism against PI3K/mTOR inhibition in colorectal cancer from a systems perspective. They found that multiple oncogenic kinases are activated to contribute to the survival of colorectal cancer cells under PI3K/mTOR blockade, and that these cells undergo pro‐tumorigenic senescence. Cotargeting PI3K/mTOR and BET exerts potent anti‐cancer activity by suppressing the activation of several resistance‐mediating kinases. The findings provide a rationale for a novel therapeutic strategy to overcome resistance to PI3K/mTOR inhibitors in colorectal cancer. [ABSTRACT FROM AUTHOR]