These cancergnaling in the presence of the TKI.67 These cancers therefore may be susceptible to addition of a PI3K pathway inhibitor to the TKI to re induce remissions. This is an attractive approach inHER2 amplifiedbreast cancers, because they appear to be sensitive to PI3K Cyclooxygenas pathway inhibitors even before they develop resistance to anti HER2 based therapies. Indeed, the HER2 amplified breast cancer cell lines with PIK3CA mutations are resistant to trastuzumab, and this can be overcome with treatment with GDC 0941.44,107 Similarly,PTENloss, or activating mutations in PIK3CA, confers resistance to lapatinib, which can be overcome by treatment with NVP BEZ235.68 Potential of Combining PI3K With MEK Pathway Inhibitors When cancers are sensitive to TKIs, the TKI usually leads to downregulation of PI3K and other pathways, including the MEK MAPK pathway.
Thus, it remains unclear whether single agent PI3K pathway inhibitors will promote dramatic responses, even in sensitive cancers. Most models of cancers that are sensitive to single agent PI3K pathway inhibitors have demonstrated tumor stasis in vivo rather than frank tumor regressions.91 93,95 97 Consequently, itmaybe necessary to combine PI3K pathway inhibitors with other agents to induce dramatic responses. Furthermore, there may be cancers that show no response to single agent PI3K pathway inhibitors that will respond to PI3K pathway inhibitors combined with other therapies. For example, inhibition of PI3K signaling with NVP BEZ235 failed to shrink established Kras G12D driven lung tumors.
65 However, combined PI3K and MAPK pathway inhibition by treatment with NVPBEZ235 and the MEK inhibitor ARRY 142886 led to marked tumor regression in this Kras lung cancer model.65 Similarly, combined PI3K and MEK inhibition was required to effectively shrink EGFR mutant lung cancers in genetically engineered mouse models.108 Findings such as these are spurring the biotechnology and pharmaceutical industries to combine therapeutic inhibitors of these two pathways. SUMMARY Great strides are being made in our understanding of the diverse roles that PI3K signaling plays in cancer initiation, progression, and maintenance. Novel therapeutics targeting different components of this pathway are demonstrating efficacy in an array of human cancer types in preclinical studies, and these drugs are being carried forward into clinical trials.
There is growing preclinical evidence that some genetically defined cancer subtypesmaybe the most sensitive to single agent PI3K pathway inhibitors. These include cancers with PIK3CA activating mutations, loss of PTEN, and breast cancers with HER2 amplification. However, it remains to be determined whether these sensitive cancers will demonstrate stable disease or tumor shrinkage in response to single agent therapeutics. Conversely, cancers harboring activated Ras mutants appear to be insensitive to PI3K pathway inhibition alone. In such cases, effective treatment with PI3K inhibitors may require conco