PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC

Thomas B. Davis; Mingli Yang; Heiman Wang; Changgong Lee; Timothy J. Yeatman; W. Jack Pledger

doi:10.18632/oncotarget.27335

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Priority Research Papers:

PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC

Thomas B. Davis, Mingli Yang, Heiman Wang, Changgong Lee, Timothy J. Yeatman _ and W. Jack Pledger _

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Oncotarget. 2019; 10:6768-6780. https://doi.org/10.18632/oncotarget.27335

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Abstract

Thomas B. Davis1, Mingli Yang1, Heiman Wang1, Changgong Lee2, Timothy J. Yeatman1^,3^,4 and W. Jack Pledger1^,3

1 Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA

2 Gibbs Cancer Center & Research Institute, Spartanburg, SC 29303, USA

3 Cell Response and Regulation Program, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA

4 Oncology Clinical Program, Intermountain Healthcare, Murray, UT 84107, USA

Correspondence to:

W. Jack Pledger,	email:	[email protected]
Timothy J. Yeatman,	email:	[email protected]

Keywords: colorectal cancer; PTPRS; ERK; SRC; adaptive resistance

Received: September 06, 2019 Accepted: November 07, 2019 Published: November 26, 2019

ABSTRACT

PTPRS is the most commonly mutated receptor tyrosine phosphatase in colorectal cancer (CRC). PTPRS has been shown to directly affect ERK and regulate its activation and nuclear localization. Here we identify that PTPRS may play a significant role in developing adaptive resistance to MEK/ERK inhibitors (MEKi/ERKi) through SRC activation. Moreover, we demonstrate a new clinical approach to averting adaptive resistance through the use of the SRC inhibitor, dasatinib. Our data suggest the potential for dasatinib to enhance the efficacy of MEKi and ERKi by preventing adaptive resistance pathways operating through SRC.

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Priority Research Papers:

PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC

Abstract