Protein Tyrosine Phosphatase Non-Receptor 11 ( PTPN11 /Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)

Cathy E Richards; Yasir Y Elamin; Aoife Carr; Kathy Gately; Shereen Rafee; Mattia Cremona; Emer Hanrahan; Robert Smyth; Daniel Ryan; Ross K Morgan; Susan Kennedy; Lance Hudson; Joanna Fay; Kenneth O'Byrne; Bryan T Hennessy; Sinead Toomey

doi:10.3390/ijms241310545

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Protein Tyrosine Phosphatase Non-Receptor 11 ( PTPN11 /Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)

Journal article

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Peer reviewed

Protein Tyrosine Phosphatase Non-Receptor 11 ( PTPN11 /Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)

Cathy E Richards, Yasir Y Elamin, Aoife Carr, Kathy Gately, Shereen Rafee, Mattia Cremona, Emer Hanrahan, Robert Smyth, Daniel Ryan, Ross K Morgan, …

International journal of molecular sciences, Vol.24(13), p.10545

06/23/2023

DOI: 10.3390/ijms241310545

PMCID: PMC10341803

PMID: 37445722

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Abstract

encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of and MEK. /Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. constructs harbouring E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. /Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a -mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype ( < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant exhibited increased /Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype . The transduction of the inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the -mutated NCI-H661 cell line. NCI-H661 cells ( -mutated, -wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 ( / -wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro ( < 0.0001). /Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting.

Adenocarcinoma - genetics

Carcinoma, Non-Small-Cell Lung - drug therapy

Carcinoma, Non-Small-Cell Lung - genetics

Carcinoma, Non-Small-Cell Lung - pathology

Cell Line, Tumor

Humans

Interleukin-3 - genetics

Lung Neoplasms - drug therapy

Lung Neoplasms - genetics

Lung Neoplasms - pathology

MAP Kinase Signaling System - genetics

Mitogen-Activated Protein Kinases - metabolism

Mutation

Oncogenes

Phosphatidylinositol 3-Kinases - metabolism

Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism

Proto-Oncogene Proteins p21(ras) - genetics

Details

Title: Subtitle: Protein Tyrosine Phosphatase Non-Receptor 11 ( PTPN11 /Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)
Creators: Cathy E Richards - Royal College of Surgeons in Ireland
Yasir Y Elamin - Royal College of Surgeons in Ireland
Aoife Carr - Royal College of Surgeons in Ireland
Kathy Gately - Trinity College Dublin
Shereen Rafee - Trinity College Dublin
Mattia Cremona - Royal College of Surgeons in Ireland
Emer Hanrahan - St. Vincent's University Hospital
Robert Smyth - Royal College of Surgeons in Ireland
Daniel Ryan - Department of Respiratory Medicine, Beaumont Hospital, D09 V2N0 Dublin, Ireland
Ross K Morgan - Beaumont Hospital
Susan Kennedy - St. Vincent's University Hospital
Lance Hudson - Royal College of Surgeons in Ireland
Joanna Fay - Royal College of Surgeons in Ireland
Kenneth O'Byrne - Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
Bryan T Hennessy - Royal College of Surgeons in Ireland
Sinead Toomey - Royal College of Surgeons in Ireland
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.24(13), p.10545
DOI: 10.3390/ijms241310545
PMID: 37445722
PMCID: PMC10341803
ISSN: 1661-6596
eISSN: 1422-0067
Grant note: N/A / North East Cancer Research and Education Trust (NECRET)
Language: English
Date published: 06/23/2023
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
Record Identifier: 9984695833302771

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