{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:06Z","timestamp":1784937606643,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Conquer Cancer Foundation Young Investigator Award (YIA)","award":["1696"],"award-info":[{"award-number":["1696"]}]},{"name":"The North East Cancer Research and Education Trust (NECRET)","award":["1696"],"award-info":[{"award-number":["1696"]}]},{"name":"the Fox and Kerin Families","award":["1696"],"award-info":[{"award-number":["1696"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11\/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 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, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 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. PTPN11\/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 PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4\/98 (4.1%) adenocarcinomas and 7\/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba\/F3 cells compared to wildtype PTPN11 (p &lt; 0.0001). Ba\/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11\/Shp2 phosphatase activity and phospho-ERK1\/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 \u00b1 4.7 nM) compared to NCI-H1703 (PTPN11\/KRAS-wild type) cells (IC50: &gt;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 (p &lt; 0.0001). PTPN11\/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.<\/jats:p>","DOI":"10.3390\/ijms241310545","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T01:42:32Z","timestamp":1687743752000},"page":"10545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["RETRACTED: Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11\/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6551-8017","authenticated-orcid":false,"given":"Cathy","family":"Richards","sequence":"first","affiliation":[{"name":"Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasir","family":"Elamin","sequence":"additional","affiliation":[{"name":"Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"},{"name":"Department of Thoracic Head and Neck Medical Oncology, Division of Cancer Medicine, M.D. Anderson Cancer Centre, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoife","family":"Carr","sequence":"additional","affiliation":[{"name":"Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Gately","sequence":"additional","affiliation":[{"name":"Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, St. James\u2019s Hospital, D08 NHY1 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shereen","family":"Rafee","sequence":"additional","affiliation":[{"name":"Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, St. James\u2019s Hospital, D08 NHY1 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Cremona","sequence":"additional","affiliation":[{"name":"Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emer","family":"Hanrahan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, St. Vincent\u2019s Hospital, D04 T6F4 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Smyth","sequence":"additional","affiliation":[{"name":"Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ryan","sequence":"additional","affiliation":[{"name":"Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"},{"name":"Department of Respiratory Medicine, Beaumont Hospital, D09 V2N0 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Beaumont Hospital, D09 V2N0 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Pathology, St. Vincent\u2019s Hospital, D04 T6F4 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance","family":"Hudson","sequence":"additional","affiliation":[{"name":"Department of Surgery, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Fay","sequence":"additional","affiliation":[{"name":"RCSI Biobank Service, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"O\u2019Byrne","sequence":"additional","affiliation":[{"name":"Princess Alexandra Hospital, Brisbane, QLD 4102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Hennessy","sequence":"additional","affiliation":[{"name":"Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinead","family":"Toomey","sequence":"additional","affiliation":[{"name":"Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, D09 YD60 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/S0025-6196(11)60735-0","article-title":"Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship","volume":"83","author":"Molina","year":"2008","journal-title":"Mayo Clin. 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