Abstract 4236: FAK inhibitor VS-6063 (defactinib) targets mesothelioma cancer stem cells, which are enriched by standard of care chemotherapy

Abstract

Abstract Malignant pleural mesothelioma (MPM) is an aggressive tumor in the lining of the lung often resulting from prior exposure to asbestos. Median overall survival with standard of care chemotherapy is only 12 months from diagnosis. This poor prognosis may be attributable at least in part to cancer stem cells (CSCs) which are resistant to chemotherapy and can mediate cancer recurrence and progression. Focal adhesion kinase (FAK) has been shown to play an essential role in the survival, self-renewal and tumor-initiating capability of CSCs. Accordingly, the FAK inhibitor VS-6063 is currently being tested in patients with MPM following disease control on standard pemetrexed/platinum chemotherapy (COMMAND, ClinicalTrials.gov NCT01870609). Aldehyde dehydrogenase (ALDH) activity was validated as a CSC marker in MPM by assessment of tumor-initiating capability in mice. As compared to ALDH-negative cells, sorted ALDH-positive MM87 MPM cells showed 35-fold greater tumor initiating capacity when implanted in limiting dilutions into immunodeficient mice. Indeed, 50 ALDH-positive cells were sufficient to generate sizeable tumors in 3 weeks illustrating the aggressive nature of MPM CSCs. Treatment of a human MPM cell line with pemetrexed enriched ALDH-positive CSCs 6-fold, with similar CSC enrichment by cisplatin. In direct contrast, the FAK inhibitor VS-6063 markedly reduced the proportion of CSCs. The enrichment of MPM CSCs was similarly observed in samples from 11 tested patients following first line chemotherapy. Patient specimens post treatment with pemetrexed and cisplatin showed an elevated ALDH immunohistochemistry H-score and an increase in expression of CSC genes such as CD133 as compared to matched MPM biopsies taken from the same patients prior to chemotherapy. To assess drug effects on tumor-initiating capacity, MM87 merlin-low MPM and H28 merlin-high MPM cell lines were treated in vitro with VS-6063, pemetrexed or the combination and subsequently implanted into mice. While control and pemetrexed-treated MPM cells showed robust tumor initiation, cells treated with VS-6063 alone or VS-6063 plus pemetrexed showed little or no tumor initiating capacity. Accordingly, in tumor biopsies from MPM patients treated for 12 days with VS-6063, tumor pFAK (Y397) and expression of CSC genes such as CD133 were reduced. MPM patient-derived xenograft (PDX) tumors were employed to model the clinical scenario. Compared to control, tumor growth was blocked by 2-week treatment with pemetrexed/cisplatin. Tumors then grew rapidly upon cessation of pemetrexed/platinum treatment, whereas tumor growth was substantially delayed by FAK inhibitor treatment after cessation of chemotherapy. These data provide strong rationale for the current clinical testing of VS-6063 following treatment with pemetrexed plus platinum to potentially prolong time to progression in patients with mesothelioma. Citation Format: Jonathan A. Pachter, Vihren N. Kolev, Laurel Schunselaar, Irina M. Shapiro, Raphael Bueno, Paul Baas, Qunli Xu, David T. Weaver. FAK inhibitor VS-6063 (defactinib) targets mesothelioma cancer stem cells, which are enriched by standard of care chemotherapy. [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 4236. doi:10.1158/1538-7445.AM2015-4236