Many chemotherapies induce cell death in a subset of tumor cells, but there remains a question of whether this death enables survival of the remaining malignant cells. Using patient-derived colorectal cancer organoids treated with the chemotherapy 5-fluorouracil, Schmitt and colleagues found efficient induction of the mechanistic target of rapamycin (mTOR) pathway in surviving cancer cells, specifically, mTOR complex 1 and its indirect target p-S6. Coadministration of the mTOR inhibitor rapamycin and 5-fluorouracil led to synergistic inhibition of cancer cell survival in organoids and xenografts. Through systematic testing in a mouse model of colorectal cancer, the authors showed that mTOR signaling was driven by paracrine release of ATP from dying cells and required the P2X4 receptor. Inhibition of P2X4, like inhibition of mTOR, greatly decreased tumor graft size when combined with 5-floururacl.
Expert Commentary: This work identifies a potential combination therapy not easily predicted by genomic alterations and suggests that profiling...
