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.