Exploring the use of tyrosine kinase inhibitors in glioblastoma and RET-rearranged lung cancer to curtail cell migration and invasion and improve therapy by understanding drug resistance

Includes bibliographical references. ; Spring ; The exponential increase in targeted tyrosine kinase inhibitor (TKI) therapies approved for use in cancer or in late-stage clinical trials has revolutionized the treatment of solid tumors over the last decade. However, many questions regarding the fundamental biology of oncogenic and wild-type receptor tyrosine kinases (RTKs) and how cancer cells adapt to become resistant to TKI therapies have been raised. This work addresses some of these questions specifically as they relate to glioblastoma (GBM) and RET fusion positive lung adenocarcinoma (LAC). First, I demonstrate the feasibility of targeting the Mer receptor tyrosine kinase (MERTK) in order to decrease glioblastoma cell migration and invasion. Using genetic knockdown and the MERTK TKIs foretinib and UNC2025, I demonstrate that MERTK inhibition decreases the migration and invasion of glioblastoma cells in two- and three dimensional in vitro assay systems. Further, I demonstrate that siRNA knockdown of MERTK inhibits expression of focal adhesion kinase (FAK), a master regulator of cell migration and invasion. Second, I demonstrate that mechanisms of acquired resistance to the RET-inhibitor ponatinib RET positive LAC result in reactivation of RAS/MAPK signaling either through the acquisition of oncogenic NRAS p.Q61K signaling or through increased dependence upon wild-type EGFR and AXL signaling. And third, I investigate the mechanisms through which combination mTOR and RET inhibition is improving patient responses to targeted therapy in RET positive LAC patients and demonstrate that while RET inhibition partially suppresses signaling through mTOR, maximal inhibition of this signaling pathway is not achieved without the addition of mTOR inhibition with everolimus. Overall, these pre-clinical studies indicate that clinically available targeted therapies can be used to enhance the inhibition of the glioblastoma cell migration and invasion, as well as to target intrinsic and acquired resistance to targeted RET ...