Researchers from The Wistar Institute have identified that sole use of inhibitors of PI3K in the cancer therapy may promote the metastasis to cause deterioration. This study was published in PNAS.

The phosphatidylinositol 3-kinase (PI3K) is a universal tumor driver that integrates growth factor signaling with downstream circuitries of cell proliferation, metabolism, and survival. Exploited in nearly every human tumor, including through acquisition of activating mutations, PI3K signaling is an important therapeutic target and several small-molecule antagonists of this pathway have entered clinical testing.

Despite the promise of personalized cancer medicine, most molecular therapies produce only modest and short-lived patient gains. In addition to drug resistance, it is also possible that tumors adaptively reprogram their signaling pathways to evade therapy-induced “stress” and, in the process, acquire more aggressive disease traits.

In this study, scientists show that small-molecule inhibitors of PI3K, a cancer node and important therapeutic target, induce transcriptional and signaling reprogramming in tumors. This involves the trafficking of energetically active mitochondria to subcellular sites of cell motility, where they provide a potent, “regional” energy source to support tumor cell invasion. Although this response may paradoxically increase the risk of metastasis during PI3K therapy, targeting mitochondrial reprogramming is feasible, and could provide a novel therapeutic strategy.