Targeting Both Pi3k/Mtor And Egfr Pathways Leads To Synergistic Anti-Tumor Activity In Erlotinib Resistant Non-Small-Cell Lung Cancers.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC NSCLCs with EGFR mutations, such as a deletion in exon 19 (del E746-A750) or point mutation in exon 21 (L858R), are sensitive to TKI (gefitinib and erlotinib) treatments. However, acquired resistance to TKI therapy occurs in patients after 12-14 months. Approximately 50% of these resistant patients have developed secondary (gatekeeper) T790M mutation in EGFR; many other resistance mechanisms also have been described including a PIK3CA mutation and PTEN deletion. In this study, we characterize a dual PI3K/mTOR inhibitor, PF-4979064, in combination with a pan-ErbB inhibitor, PF-299804 (dacomitinib) in erlotinib resistant NSCLC lines NCI-H1975 (harboring EGFR and PIK3CA mutation) and NCI-H1650 (harboring EGFR and PTEN deletion). As a clinically relevant concentration of PF-299804 only induces moderate anti-tumor activity in both H1975 and H1650 cells, PF-4979064 was added in a variety of cellular and animal studies to determine whether the combination was able to achieve a synergistic induction of anti-tumor activity. Results demonstrate that the combination of PF-4979064 and PF-299804 lead to a synergistic inhibition in cell proliferation and xenograft tumor growth in both the NCI-H1975 and NCI-H1650 models. Our results further suggest that there is a rationale to examine a potential clinical development plan combining the dual PI3K/mTOR inhibitor (PF-4979064) and dacomitinib (PF-299804) in NSCLC patients who have developed resistance to erlotinib and have a concomitant PIK3CA mutation or PTEN deletion. Citation Format: Pramod P. Mehta, Sangita M. Baxi, Marlena Walls, Stella Chen, Hengmiao Cheng, Gang Li, Tod Smeal, Min-Jean Yin. Targeting both PI3K/mTOR and EGFR pathways leads to synergistic anti-tumor activity in erlotinib resistant non-small-cell lung cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4467. doi:10.1158/1538-7445.AM2013-4467