Mutant smoothened and methods of using 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 theserpentine 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 SMOmaintain Hh signaling, but result in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. In some embodiments, the disclosure provides for novel mutant SMO proteins and nucleic acids and for screening metliods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

Description

[0001] related application [0002] This patent application claims priority to US Provisional Application Serial No. 62 / 112,074, filed February 4, 2015. The disclosure of the aforementioned application is hereby incorporated by reference in its entirety. Background technique [0003] Molecularly targeted cancer therapies have shown impressive activity in the clinic. Some of the best known examples include the tyrosine kinase inhibitor imatinib in Philadelphia chromosome-positive chronic myeloid leukemia (CML) or KIT / PDGFR-mutant gastrointestinal stromal tumors (GIST) and EGFR-mutant non-small Erlotinib in NSCLC (Krause, D.S. and R.A. Van Etten (2005) N. Engl. J. Med. 353(2):172-187). Treatment with these agents has resulted in significant antitumor responses in patient populations with these molecular abnormalities. However, despite impressive initial clinical responses, a large proportion of patients eventually progress due to the acquisition of drug resistance (Engelman,...

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However, it is unclear which mechanism drives resistance in patients

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