Genentech, Inc.

Curis, Inc.

Other

Assistance Publique-Hopitaux De Paris

Osi Pharmaceuticals, Inc.

Université Paris Diderot-Paris 7

Robert L Yauch

Frederic J De Sauvage

John D Haley

Graeme Griffin

Thomas E Januario

Lukas A Amler

Avi J Ashkenazi

Lukas C Amler

Gerrit J P Dijkgraaf

David A Eberhard

Xiaofen Ye

Premal Patel

Hayley Sharpe

Gerrit Jp Dijkgraaf

Nicole Basset-Seguin

Gerrit JP Dijkgraaf

Gerrit JP Dijkraaf

Amy C Peterson

Jiping Zha

Thomas Januario

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.

Mutant smoothened and methods of using the same

Provided herein are combination therapies for the treatment of pathological conditions, such as cancer, using an antagonist of FGFR signaling.

Methods of treating and preventing cancer drug resistance

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.

The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.

Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors

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Redwood City, CA, United States of America

Robert L Yauch