predominantly via its effects on mTORC1, not mTORC2.106 Both PP242 and Torin1 were more effective inhibitors of 4E BP1 phosphorylation and cap dependent RNA translation than rapamycin.103,105,106 Three additional ATP competitive mTOR inhibitors WAY 600, WYE 687, and WYE 354 have been shown to inhibit proliferation CYC116 of a variety of cancer cell lines more effectively than rapamycin, causing G1 cell cycle arrest, and in some cases, apoptosis.104 Although the clinical results with PI3K pathway inhibitors are preliminary, their efficacy has modest at best. For their effective development, it will be imperative to understand why these drugs fail to produce a response when they do.
Is the lack of activity due to inadequate inhibition of the target, or because complete inhibition of the target is not sufficient to produce antitumor activity? Indeed, most of the studies to date have not assessed this issue systematically. To answer this question, future studies with quantitative pharmacodynamic assessments will be required to determine the degree of target inhibition. For example, a study with even a small number of patients with favorable genotypes that correlates pharmacodynamic responses of PI3K pathway inhibition with outcomes may prove invaluable in identifying the reasons for lack of efficacy. POTENTIAL CLINICAL USES FOR PI3K PATHWAY INHIBITORS Thus far, preclinical studies have shown that PI3K pathway inhibitors may have significant single agent activity in a few types of genetically defined cancers: HER2 amplified breast cancers, cancers with PIK3CA mutations, and PTEN deficient cancers.
65,77,92,93,101 To this point, data suggest that cancers with KRAS mutations may be fairly resistant to PI3K pathway inhibitors.65,77 Consequently, it seems likely that the presence of KRAS mutations will limit the efficacy of single agent PI3K pathway inhibitors in cancers harboring bothKRAS and PIK3CA mutations, such as many colon cancers. In addition to these genetically defined settings, there may be other opportunities to target the PI3K pathway. For example, PI3K pathway inhibitors may be effective agents in the treatment of certain cancers that acquire resistance to RTK inhibitors. Cancers that are sensitive to receptor tyrosine kinase inhibitors have PI3K under the exclusive control of that RTK.
67 When a TKI works, it leads to downregulation of PI3K activity. For example in HER2 amplified breast cancers, trastuzumab disrupts the interaction between ErbB2 and ErbB3, resulting in ErbB3 dephosphorylation and loss of interaction with PI3K.107 Furthermore, the presence of an activating PIK3CA mutation or depletion of PTEN correlates with a poor response to trastuzumab, presumably because these cancers fail to downregulate PI3K signaling in response to the anti HER2 therapy. Furthermore, whencancers that were initially sensitive to TKIs subsequently develop resistance, they invariably find a way to maintain PI3K si