Genentech, Inc.

Curis, Inc.

Thomas E Januario

Frederic J De Sauvage

Robert L Yauch

David Shames

Gerrit J P Dijkgraaf

Gerrit Jp Dijkgraaf

The present invention provides methods of treating cancer based on the methylation status of the ERBB2 gene. One aspect of the invention provides a method of administering an EGFR inhibitor therapy based on the methylation status of the ERBB2 gene.

Methods for diagnosing and treating cancer

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, we describe a mutation in the serpentine receptor, Smoothened (SMO), which results in resistance to a Hedgehog (Hh) pathway inhibitor in medulloblastoma. A single amino acid substitution in a conserved aspartic acid residue of SMO maintains Hh signaling, but results in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. This mutation was not only acquired in a GDC-0449-resistant mouse model of medulloblastoma, but was identified in a Medulloblastoma patient following relapse on GDC-0449. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

Mutant smoothened and methods of using the same

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San Francisco, CA, United States of America

Thomas E Januario