Proposed mechanisms accounting for resistance to inhibitors of the PI3K pathway. ➀ Selective blockade of mTORC1 by rapalogs increases mTORC2 and results in the positive feedback activation of pAkt. ➁ Inhibition of mTOR removes the basal inhibition of IRS-1, which is now free to bind to and activate IGF-1R and promote PI3K activation. ➂ In the presence of constitutive activation of KRAS, abrogation of the PI3K pathway alone does not inhibit cancer cell growth. IRS-1, insulin receptor substrate-1. Other abbreviations as in Figure 1.