Abstract 1525: FAK and PI3K/mTOR inhibitors target cancer stem cells: Implications for SCLC treatment strategies

Abstract

Abstract Small cell lung cancer (SCLC) is an extremely aggressive cancer with poor outcome. In most patients with SCLC tumors initially respond to first line chemotherapy, but subsequently experience aggressive recurrence that may be attributed to the presence of a cancer stem cell (CSC) population with tumor-initiating and metastatic potential. Inhibitors of FAK and PI3K/mTOR have been shown to preferentially target CSCs in preclinical models of other cancers, where the evidence indicates that CSC populations are increased following chemotherapy. FAK and PI3K/mTOR inhibitors may be particularly valuable in a SCLC setting, where CSCs may be strong mediators of recurrence. Tumors of patients with SCLC are generally not resectable, such that tumor biopsies are not available for CSC evaluation. Therefore, it will be important to be able to monitor CSC markers by blood-based testing. A drug-resistant population of SCLC CSCs (side population, SP) can be monitored by enhanced ability to exclude Hoechst 33342 dye. Additionally, SCLC CD133+ cells have been demonstrated to possess CSC properties and presence of CD133+ cells in SCLC has been linked to poor prognosis. Our data indicate that cisplatin and etoposide, first line chemotherapy for SCLC, enrich for SP and CD133+ cells, suggesting that chemotherapy is not effective against CSCs and should be combined with anti-CSC agents for more durable response. Here we investigate the antitumor activity of FAK and PI3K/mTOR inhibitors in SCLC xenograft models in vivo. Both a FAK inhibitor (VS-4718) and PI3K/mTOR inhibitor (VS-5584) were found to enhance the antitumor activity of chemotherapy in an NCI-H69 SCLC xenograft model. Additionally, oral administration of VS-5584 reduced the proportion of CSCs in vivo in an NCI-H841 SCLC tumor model as evidenced by a decrease in the percentage of SP cells and approximately 70-fold reduction in in vivo tumor-initiating capability. The combination of chemotherapy and FAK or PI3K/mTOR inhibitors demonstrate an extended time to relapse after first line therapy. VS-5584 significantly delayed tumor regrowth following cessation of cisplatin treatment in H69 xenograft tumors and a SCLC patient-derived xenograft (PDX) model. Patients with relapsed SCLC have elevated circulating tumor cells, consistent with the poor prognosis of their disease status. Blood samples from these patients are under evaluation for CSC markers in the circulation. The preferential targeting of CSCs in preclinical SCLC models provides an important rationale for clinical development of FAK and PI3K inhibitors, where combination with chemotherapeutic agents or single agent activity post chemotherapy may potentially lengthen the time to relapse and improve outcome for patients with small cell lung cancer. Citation Format: Vihren N. Kolev, Qunli Xu, Jonathan A. Pachter, David T. Weaver. FAK and PI3K/mTOR inhibitors target cancer stem cells: Implications for SCLC treatment strategies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1525. doi:10.1158/1538-7445.AM2015-1525