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TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors

51 Pages Posted: 17 Dec 2019 Sneak Peek Status: Review Complete

See all articles by Emiliano Cocco

Emiliano Cocco

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

Ji Eun Lee

Memorial Sloan Kettering Cancer Center - Cancer Biology and Genetics Program

Srinivasaraghavan Kannan

Agency for Science, Technology and Research (A*STAR) - Bioinformatics Institute

Alison M. Schram

Memorial Sloan Kettering Cancer Center - Department of Medicine

Helen Won

Memorial Sloan Kettering Cancer Center - Center for Molecular Oncology

Sophie Shifman

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

Amanda Kulick

Memorial Sloan Kettering Cancer Center - Antitumor Assessment Core Facility

Laura Baldino

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

Eneda Toska

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

Sabrina Arena

University of Torino - Department of Oncology

Benedetta Mussolin

FPO-IRCCS - Candiolo Cancer Institute

Ram Kannan

Memorial Sloan Kettering Cancer Center - Cancer Biology and Genetics Program

Neil Vasan

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

Alexander N. Gorelick

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

Michael F. Berger

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

Yi Liao

H. Lee Moffitt Cancer Center and Research Institute - Department of Drug Discovery

Uwe Rix

H. Lee Moffitt Cancer Center and Research Institute - Department of Drug Discovery

Alberto Bardelli

University of Torino - Department of Oncology

Jacklyn Hechtman

Memorial Sloan Kettering Cancer Center - Department of Pathology

Elisa de Stanchina

Memorial Sloan Kettering Cancer Center - Antitumor Assessment Core Facility

David M. Hyman

Memorial Sloan Kettering Cancer Center - Department of Medicine

Chandra Verma

Agency for Science, Technology and Research (A*STAR) - Bioinformatics Institute

Andrea Ventura

Memorial Sloan Kettering Cancer Center - Cancer Biology and Genetics Program

Alexander Drilon

Memorial Sloan Kettering Cancer Center - Department of Medicine

Maurizio Scaltriti

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

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Abstract

On-target resistance to next-generation kinase inhibitors, drugs specifically designed to maintain potency in the setting of kinase domain mutations, remains poorly characterized. Having identified that xDFG (TRKA G667) mutations confer second-generation TRK inhibitor resistance in patients with TRK fusion-positive cancers, we used computational modeling and biochemical assays to study how these affect drug binding. We found that xDFG mutations stabilize the inactive kinase conformation, hampering the binding of type I second-generation TRK inhibitors, while increasing the affinity for type II multikinase inhibitors. Type II drugs consistently inhibit the growth and TRK-mediated signaling of isogenic and patient-derived models harboring xDFG mutations. Collectively these data demonstrate that TRK xDFG substitutions trigger conformational changes that favor type II binding mechanisms. Given prior identification of paralogous xDFG resistance mutations in other oncogene addicted cancers, these findings provide insight into rational drug design to address these recalcitrant resistant alterations by leveraging inhibitor class affinity switching.

Keywords: drug resistance, tyrosine kinase inhibitors, cancer, signaling

Suggested Citation

Cocco, Emiliano and Lee, Ji Eun and Kannan, Srinivasaraghavan and Schram, Alison M. and Won, Helen and Shifman, Sophie and Kulick, Amanda and Baldino, Laura and Toska, Eneda and Arena, Sabrina and Mussolin, Benedetta and Kannan, Ram and Vasan, Neil and Gorelick, Alexander N. and Berger, Michael F. and Liao, Yi and Rix, Uwe and Bardelli, Alberto and Hechtman, Jacklyn and de Stanchina, Elisa and Hyman, David M. and Verma, Chandra and Ventura, Andrea and Drilon, Alexander and Scaltriti, Maurizio, TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors (December 11, 2019). CELL-D-19-03416. Available at SSRN: https://ssrn.com/abstract=3501844 or http://dx.doi.org/10.2139/ssrn.3501844
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Emiliano Cocco

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

United States

Ji Eun Lee

Memorial Sloan Kettering Cancer Center - Cancer Biology and Genetics Program

United States

Srinivasaraghavan Kannan

Agency for Science, Technology and Research (A*STAR) - Bioinformatics Institute

30 Biopolis Street
#07-01 Matrix
Singapore, 138671
China

Alison M. Schram

Memorial Sloan Kettering Cancer Center - Department of Medicine

New York, NY 10065
United States

Helen Won

Memorial Sloan Kettering Cancer Center - Center for Molecular Oncology

United States

Sophie Shifman

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

United States

Amanda Kulick

Memorial Sloan Kettering Cancer Center - Antitumor Assessment Core Facility

United States

Laura Baldino

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

United States

Eneda Toska

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

United States

Sabrina Arena

University of Torino - Department of Oncology

Italy

Benedetta Mussolin

FPO-IRCCS - Candiolo Cancer Institute

Candiolo
Italy

Ram Kannan

Memorial Sloan Kettering Cancer Center - Cancer Biology and Genetics Program

United States

Neil Vasan

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

United States

Alexander N. Gorelick

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

United States

Michael F. Berger

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program

United States

Yi Liao

H. Lee Moffitt Cancer Center and Research Institute - Department of Drug Discovery

United States

Uwe Rix

H. Lee Moffitt Cancer Center and Research Institute - Department of Drug Discovery

United States

Alberto Bardelli

University of Torino - Department of Oncology

Italy

Jacklyn Hechtman

Memorial Sloan Kettering Cancer Center - Department of Pathology

New York, NY
United States

Elisa De Stanchina

Memorial Sloan Kettering Cancer Center - Antitumor Assessment Core Facility

United States

David M. Hyman

Memorial Sloan Kettering Cancer Center - Department of Medicine

New York, NY 10065
United States

Chandra Verma

Agency for Science, Technology and Research (A*STAR) - Bioinformatics Institute

30 Biopolis Street
#07-01 Matrix
Singapore, 138671
China

Andrea Ventura

Memorial Sloan Kettering Cancer Center - Cancer Biology and Genetics Program

United States

Alexander Drilon

Memorial Sloan Kettering Cancer Center - Department of Medicine

New York, NY 10065
United States

Maurizio Scaltriti (Contact Author)

Memorial Sloan Kettering Cancer Center - Human Oncology and Pathogenesis Program ( email )

United States

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