Research ArticleCancer

mTORC1 Inhibition Is Required for Sensitivity to PI3K p110α Inhibitors in PIK3CA-Mutant Breast Cancer

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Science Translational Medicine  31 Jul 2013:
Vol. 5, Issue 196, pp. 196ra99
DOI: 10.1126/scitranslmed.3005747

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Caveat mTOR

In recent years, numerous new drugs have been developed to take advantage of specific molecular changes in cancer cells. Unfortunately, tumors are often a step ahead of the scientists, becoming resistant to these targeted drugs just when they seem to be working perfectly. Now, two groups of researchers have developed rational combination treatments that block resistance to targeted cancer drugs by inhibiting mTOR.

Elkabets and coauthors were working on breast cancer, where the PIK3CA gene is frequently mutated. Inhibitors of PI3K (the protein product of PIK3CA) are currently in clinical trials, but some of the cancers are resistant to these drugs. The authors have discovered that breast cancers resistant to the PI3K inhibitor BYL719 had persistently active mTOR signaling, both in cultured cell lines and in patient tumors. Adding an mTOR inhibitor to the treatment regimen could reverse the resistance and kill the tumor cells.

Corcoran et al. found a similar mTOR-dependent drug resistance mechanism to be active in melanoma as well. BRAF-mutant melanomas, the most common type, are frequently treated with RAF and MEK inhibitors, but only with mixed results, because melanomas quickly develop resistance to these drugs. Now, the authors have shown that drug-resistant melanomas also have persistent activation of mTOR, and adding an mTOR inhibitor to the treatment regimen can block drug resistance and kill the cancer cells.

In both studies, the activation of mTOR in drug-resistant tumors has been confirmed in human patients, but the combination treatments have only been tested in cells and in mouse models thus far. Thus, the next critical step would be to confirm that adding mTOR inhibition to treatment regimens for these cancers is effective in the clinical setting as well. Some mTOR inhibitors are already available for use in patients, so hopefully soon mTOR activation will not be something to beware of, but something to monitor and target with specific drugs.

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