Mutant smoothened and methods of using the same

Abstract

The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, mutations in the serpentine receptor, Smoothened (SMO) are described, which result in resistance to a Hedgehog (Hh) pathway inhibitor, such as in medulloblastoma. Amino acid substitutions in conserved residues of SMO maintain Hh signaling, but result in the inability of the Hh pathway inhibitor, GDC-0449, to suppress the pathway. In some embodiments, the disclosure provides for novel mutant SMO proteins and nucleicacids and for screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

Description

technical field [0001] This application claims priority to US Provisional Patent Application Serial No. 62 / 291,346, filed February 4, 2016. The disclosures of the aforementioned applications are incorporated herein by reference in their entirety. Background technique [0002] Molecularly targeted cancer therapy has shown strong activity in the clinic. Some of the most notable examples include the tyrosine kinase inhibitor imatinib in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) or kit / PDGFR-mutant gastrointestinal stromal tumor (GIST) and EGFR Erlotinib in mutant non-small cell lung cancer (NSCLC) (Krause, D.S. and R.A. Van Etten (2005) N. Engl. J. Med 353(2):172-187) . Treatment with these agents has produced dramatic antitumor responses in patient populations with these molecular abnormalities. However, despite impressive initial clinical responses, most patients eventually develop disease due to the development of drug resistance (Engelman, J.A....

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However, it is unclear which mechanism drives resistance in patients

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