Rational combinations of mTOR inhibitors as anticancer strategies

Mammalian target of rapamycin (mTOR) inhibitors have shown to be active in different malignancies and have reached daily practice. However results are still modest with stabilizations as the most frequent response and ultimately disease progression in all cases. Several feedback loops have been described that could affect the efficacy of these drugs. First, mTOR complex 2 (mTORC2) is known to be resistant to the inhibition by rapamycin analogs leading to a direct activation of Akt. Second, repression of Akt activity by different PI3K/Akt/mTOR inhibitors releases the activity of transcriptional factors that promote the expression of several receptor tyrosine kinases (RTKs). These RTKs will finally stimulate the PI3K/Akt/mTOR pathway and the mitogen-activated protein kinase (MAPK) pathway. Third, any significant decrease in pS6 levels, the final step of the PI3K/Akt/mTOR pathway, may depress the insulin receptor substrate 1 (IRS-1) leading to MAPK activation through PI3K. In order to overcome such resistance, rapalogs have been combined with different compounds that block some of these escape routes. Additionally new drugs able to inhibit simultaneously different steps of the PI3k/Akt/mTOR pathway have been developed.