Correlating Phosphatidylinositol 3-Kinase Inhibitor Efficacy with Signaling Pathway Status: In silico and Biological Evaluations

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers, and several agents targeting this pathway including PI3K/Akt/mammalian target of rapamycin inhibitors have recently entered clinical trials. One question is whether the efficacy of a PI3K pathway inhibitor can be predicted based on the activation status of pathway members. In this study, we examined the mutation, expression, and phosphorylation status of PI3K and Ras pathway members in a panel of 39 pharmacologically well-characterized human cancer cell lines (JFCR39). Additionally, we evaluated the in vitro efficacy of 25 PI3K pathway inhibitors in addition to conventional anticancer drugs, combining these data to construct an integrated database of pathway activation status and drug efficacies (JFCR39-DB). In silico analysis of JFCR39-DB enabled us to evaluate correlations between the status of pathway members and the efficacy of PI3K inhibitors. For example, phospho-Akt and KRAS/BRAF mutations prominently correlated with the efficacy and the inefficacy of PI3K inhibitors, respectively, whereas PIK3CA mutation and PTEN loss did not. These correlations were confirmed in human tumor xenografts in vivo, consistent with their ability to serve as predictive biomarkers. Our findings show that JFCR39-DB is a useful tool to identify predictive biomarkers and to study the molecular pharmacology of the PI3K pathway in cancer. Cancer Res; 70(12); 4982-94. ©2010 AACR.

PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs

“…As a group, mTOR inhibitor sensitive PIK3CA-mutated breast cancer cell lines did not display increased MAPK pathway activation upon treatment with everolimus or PP242. There is burgeoning evidence to demonstrate that breast cancer cells harbouring PIK3CA mutations are physiologically dependent on this kinase for the activation of RPS6 and survival, whereas PIK3CA wild-type cell lines do not necessarily require PI3K for the activation of the mTOR pathway (Crowder et al, 2009;Dan et al, 2010). These observations suggest a greater dependency of PIK3CA mutant cell lines to the canonical PI3K-AKT-mTOR pathway, which is consistent with our observations.…”

“…Ctrl, control; MDA, MDA-MB; null, loss of function; wt, wild type; *HER2 amplification. (Dan et al, 2010). On the other hand, PIK3CA mutations were recently reported to predict sensitivity to everolimus in glioblastoma, breast, ovarian, prostate, endometrial and colorectal cancer cells (Di Nicolantonio et al, 2010), to predict response to temsirolimus alone or in combination in patients with advanced cervical, endometrial, ovarian and breast cancer in a phase I clinical trial (Janku et al, 2011), and the PI3K/mTOR dual inhibitor NVP-BEZ235 has been shown to selectively induce cell death in breast cancer cells harbouring PIK3CA mutations (Serra et al, 2008;Brachmann et al, 2009) but not in cells lacking PTEN function (Brachmann et al, 2009).…”

Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

“…Identical observations were made for the pan-class I PI3K inhibitor GDC-0941, in an analysis restricted to a panel of 54 breast cancer lines (38). However, another study conducted with different PI3K inhibitors carried out in a panel of 39 lines from 9 different lineages did not show enhanced activity in either PIK3CA or PTEN mutant lines (39). These conflicting data might reflect the fact that, in the latter study, only a small number of lines for each lineage and genetic alteration were analyzed, with a strong imbalance in the representation of each characteristic.…”

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

“…The in vivo anti-angiogenic effect is attributed to its dual inhibition mechanism: inhibition of VEGF secretion by cancer cells and direct inhibition of PI3K in endothelial cells [67] . Oral administration of ZSTK474 indicated favorable in vivo antitumor efficacy on various cancer xenografts at both early and advanced stages, without any obvious toxicity [66][67][68] ( Figure 4C). The expression of phospho-Akt (ser 473) correlates with antitumor efficacy, suggesting this could act as a predictive biomarker [68] .…”

“…Oral administration of ZSTK474 indicated favorable in vivo antitumor efficacy on various cancer xenografts at both early and advanced stages, without any obvious toxicity [66][67][68] ( Figure 4C). The expression of phospho-Akt (ser 473) correlates with antitumor efficacy, suggesting this could act as a predictive biomarker [68] . Given the favorable preclinical antitumor effect and safety of ZSTK474, the FDA of USA has recently approved the evaluation of this drug candidate in phase I clinical trials.…”