Abstract 165: Cancer stem cell phenotypes determine mechanisms of resistance to targeted therapies
Authors: George Joshy , Chen Yaohui , Yamamoto Keiko , Adamson Scott , Chuang Jeff , Yun Kyuson 
Published: August 2018

Despite promising, and sometimes dramatic, efficacy of targeted therapies, primary and acquired resistance to targeted therapies limits their broad and long-term use in the clinic. Therefore, the ability to rationally design anticipatory or combination therapies as early in the treatment process as possible could significantly improve the utility of targeted therapies and cancer outcome. Here, we report that one can predict a priori the types of mutations that will occur in SHH pathway inhibitor treated medulloblastomas based on different cancer stem cell (CSC) phenotypes in each tumor. CSCs are a subset of cancer cells that are more resistant to cytotoxic therapies (chemo and radiation) than bulk tumor cells, and are responsible for tumor recurrence. Previously, we reported that cell-of-origin is a major driver of CSC phenotypes. In particular, we showed that CSCs retain epigenetic memory of their cells-of-origin and the mitogenic pathways that drive CSC proliferation and survival are reflective of their cells-of-origin. We also demonstrated that CSCs and bulk tumor cells do not necessarily depend on the same mitogenic/survival signaling pathways. An important implication of this finding is that targeted therapies selected based on bulk tumor analyses may not be effective in ablating CSCs in some tumors. Furthermore, the selective pressure imposed on CSCs in individual patient tumors by a targeted therapy will vary greatly, depending on whether the selected drug targets a critical pathway in CSCs and not just bulk tumor cells. Another clinically significant implication is that based on the resident CSC phenotype, we may able to predict whether individual SHH tumors will or will not acquire treatment-induced mutations in the SHH pathway upon SHH pathway inhibitors (SMOi) treatment. To test this hypothesis, we treated allografts of spontaneous Ptch;p53 mouse medulloblastomas arising from different cells-of-origins with SMOi's (LDE225 and GDC0449). While all tumors responded to SMOi's initially, most acquired resistance over time. We took an integrated genomics approach to identify molecular mechanisms of therapy resistance in these SMOi-resistant tumors. We report that acquired mutations in SHH pathway genes occurred only in tumors that contained CSCs that depended on the SHH pathway. In tumors where only the bulk tumor cells, but not CSCs, depended on SHH signaling, no acquired mutations in SHH pathway genes were detected. In sum, we report that CSCs drive mechanisms of therapy resistance and also provide the first proof-of-principle evidence that it is possible to predict the types of mutations that will occur in therapy-resistant tumors in advance of treatment, which can be exploited to design anticipatory therapies in the future.

Citation Format: Joshy George, Yaohui Chen, Keiko Yamamoto, Scott Adamson, Jeff Chuang, Kyuson Yun. Cancer stem cell phenotypes determine mechanisms of resistance to targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 165.