She et al. showed that this approach inhibited growth of breast cancer xenografts, which was not seen with either EGFR inhibition or PTEN induction alone . Similar benefits have been observed in NSCLC, prostate, and leukemia cell lines, thereby linking PTEN status and Akt activity with sensitivity to EGFR inhibition . In PTEN null gefitinib resistant cells, reintroduction of PTEN function or treatment with LY restores gefitinib sensitivity . Lots of distinct PIK inhibitors can restore sensitivity to EGFR inhibitors . Sordella et al. identified that NSCLC cells transfected with gefitinib sensitizing EGFR mutations had improved levels of activated Akt, and these cells had been even more sensitive than their wild type counterparts not only to gefitinib, but additionally to LY . In a different study with PX , a PIK inhibitor selective for p , PX was in a position to abolish gefitinib resistance in NSCLC xenografts. Toxicities associated with PX administration have been decreased glucose tolerance and hyperglycemia, both of which have been reversed upon discontinuation of drug therapy .
Synergistic effects of rapamycin and EGFR TKIs happen to be observed in Y-27632 clinical trial a few in vitro systems, including glioblastoma multiforme , prostate cancer , pancreatic cancer , squamous cell carcinoma , renal cell carcinoma , leukemia , cervical carcinoma , and non smaller cell lung cancer . Many of these studies extended the efficacy of these combinations to xenograft experiments . Buck et al. noted re sensitization and synergistic growth inhibition with the mixture of rapamycin and erlotinib in cells lines that were previously resistant to erlotinib . Li et al. noted considerable regression of lung tumors in transgenic mice that possessed the secondary resistance mutation TM when treated with the mixture of rapamycin and also the irreversible EGFR TKI, HKI . In human glioma cell lines with mutant PTEN, addition from the dual PIK mTOR inhibitor PI to erlotinib was required to induce growth arrest, suggesting that activation with the PIK Akt mTOR pathway by EGFR independent mechanisms confers resistance to EGFR inhibitors, which can nonetheless be overcome by the addition of pathway inhibitors.
Collectively, these data recommend that the usage of EGFR antagonists with pathway inhibitors may possibly be particularly useful in individuals whose tumors harbor mutations in EGFR and or PTEN, also as individuals that have developed resistance to EGFR TKIs. Combinations with erbB antagonists. Yet another potentially useful mixture is proximal inhibition of erbB, also referred to as her neu, with distal inhibition of Akt or mTOR. Inhibition of Akt phosphorylation is usually a requirement for the anti Nilotinib proliferative effects of the her neu antagonist, trastuzumab, and trastuzumab resistant cells exhibit sustained activation in the PIK Akt mTOR pathway .