Even in tumor types such as renal cell or pancreatic neuroendocrine cancers where mTOR
inhibitors have demonstrated sufficient clinical benefit to justify FDA approval, objective tumor
responses are sporadic[56]. Some researchers have hypothesized that tumor shrinkage
in response to mTOR inhibitors requires a functional apoptotic machinery. Majumder et al
demonstrated that rapamycin-resistant SKOV3 ovarian cells have an activated PI3K pathway
but upregulated levels of the anti-apoptotic protein, bcl2, and bcl2 knock-down using
siRNA restored rapamycin sensitivity[57]. In line with this preclinical data, the Phase I trial
of the Akt inhibitor perifosine reported compensatory increases in bcl2 in post treatment tumor
biopsies