MUTANT SMOOTHENED AND METHODS OF USING THE SAME

摘要

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 bind SMO and suppress the pathway. In some embodiments, the disclosure provides for novel mutant SMO proteins and nucleic acids and for screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

主权项

1. An isolated nucleic acid molecule encoding a mutant SMO protein comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 1 wherein said amino acid sequence comprises:
a) an amino acid other than tryptophan at the amino acid position corresponding to position 281 of SEQ ID NO: 1; b) an amino acid other than alanine at the amino acid position corresponding to position 459 of SEQ ID NO: 1; c) an amino acid other than tryptophan at the amino acid position corresponding to position 535 of SEQ ID NO: 1; and/or d) an amino acid other than isoleucine at the amino acid position corresponding to position 408 of SEQ ID NO: 1.