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Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1

Preclinical and clinical studies have evidenced that effective targeted therapy treatment designed against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, reactivation of e...

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Autores principales: Kurupi, Richard, Floros, Konstantinos V., Jacob, Sheeba, Chawla, Ayesha T., Cai, Jinyang, Hu, Bin, Puchalapalli, Madhavi, Coon, Colin M., Khatri, Rishabh, Crowther, Giovanna Stein, Egan, Regina K., Murchie, Ellen, Greninger, Patricia, Dalton, Krista M., Ghotra, Maninderjit S., Boikos, Sosipatros A., Koblinski, Jennifer E., Harada, Hisashi, Sun, Yue, Morgan, Iain M., Basu, Devraj, Dozmorov, Mikhail G., Benes, Cyril H., Faber, Anthony C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728803/
https://www.ncbi.nlm.nih.gov/pubmed/36506869
http://dx.doi.org/10.1158/2767-9764.CRC-21-0137
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author Kurupi, Richard
Floros, Konstantinos V.
Jacob, Sheeba
Chawla, Ayesha T.
Cai, Jinyang
Hu, Bin
Puchalapalli, Madhavi
Coon, Colin M.
Khatri, Rishabh
Crowther, Giovanna Stein
Egan, Regina K.
Murchie, Ellen
Greninger, Patricia
Dalton, Krista M.
Ghotra, Maninderjit S.
Boikos, Sosipatros A.
Koblinski, Jennifer E.
Harada, Hisashi
Sun, Yue
Morgan, Iain M.
Basu, Devraj
Dozmorov, Mikhail G.
Benes, Cyril H.
Faber, Anthony C.
author_facet Kurupi, Richard
Floros, Konstantinos V.
Jacob, Sheeba
Chawla, Ayesha T.
Cai, Jinyang
Hu, Bin
Puchalapalli, Madhavi
Coon, Colin M.
Khatri, Rishabh
Crowther, Giovanna Stein
Egan, Regina K.
Murchie, Ellen
Greninger, Patricia
Dalton, Krista M.
Ghotra, Maninderjit S.
Boikos, Sosipatros A.
Koblinski, Jennifer E.
Harada, Hisashi
Sun, Yue
Morgan, Iain M.
Basu, Devraj
Dozmorov, Mikhail G.
Benes, Cyril H.
Faber, Anthony C.
author_sort Kurupi, Richard
collection PubMed
description Preclinical and clinical studies have evidenced that effective targeted therapy treatment designed against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, reactivation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found head and neck squamous cell carcinoma (HNSCC) was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCCs, resulting in downregulation of mTORC signaling and antitumor effects across several HNSCC mouse models, including an human papillomavirus (HPV+) patient-derived xenograft. Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2–GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. In the presence of SHP2 inhibitor, HNSCCs are highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin. SIGNIFICANCE: This work identifies a novel role of SHP2 inhibitor by dual downregulation of PI3K and MEK pathways, through loss of GAB1 activation and disruption of GAB1 complexes in low-epiregulin HNSCC.
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spelling pubmed-97288032023-03-14 Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1 Kurupi, Richard Floros, Konstantinos V. Jacob, Sheeba Chawla, Ayesha T. Cai, Jinyang Hu, Bin Puchalapalli, Madhavi Coon, Colin M. Khatri, Rishabh Crowther, Giovanna Stein Egan, Regina K. Murchie, Ellen Greninger, Patricia Dalton, Krista M. Ghotra, Maninderjit S. Boikos, Sosipatros A. Koblinski, Jennifer E. Harada, Hisashi Sun, Yue Morgan, Iain M. Basu, Devraj Dozmorov, Mikhail G. Benes, Cyril H. Faber, Anthony C. Cancer Res Commun Research Article Preclinical and clinical studies have evidenced that effective targeted therapy treatment designed against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, reactivation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found head and neck squamous cell carcinoma (HNSCC) was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCCs, resulting in downregulation of mTORC signaling and antitumor effects across several HNSCC mouse models, including an human papillomavirus (HPV+) patient-derived xenograft. Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2–GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. In the presence of SHP2 inhibitor, HNSCCs are highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin. SIGNIFICANCE: This work identifies a novel role of SHP2 inhibitor by dual downregulation of PI3K and MEK pathways, through loss of GAB1 activation and disruption of GAB1 complexes in low-epiregulin HNSCC. American Association for Cancer Research 2022-09-26 /pmc/articles/PMC9728803/ /pubmed/36506869 http://dx.doi.org/10.1158/2767-9764.CRC-21-0137 Text en © 2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
Kurupi, Richard
Floros, Konstantinos V.
Jacob, Sheeba
Chawla, Ayesha T.
Cai, Jinyang
Hu, Bin
Puchalapalli, Madhavi
Coon, Colin M.
Khatri, Rishabh
Crowther, Giovanna Stein
Egan, Regina K.
Murchie, Ellen
Greninger, Patricia
Dalton, Krista M.
Ghotra, Maninderjit S.
Boikos, Sosipatros A.
Koblinski, Jennifer E.
Harada, Hisashi
Sun, Yue
Morgan, Iain M.
Basu, Devraj
Dozmorov, Mikhail G.
Benes, Cyril H.
Faber, Anthony C.
Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1
title Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1
title_full Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1
title_fullStr Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1
title_full_unstemmed Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1
title_short Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1
title_sort pharmacologic inhibition of shp2 blocks both pi3k and mek signaling in low-epiregulin hnscc via gab1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728803/
https://www.ncbi.nlm.nih.gov/pubmed/36506869
http://dx.doi.org/10.1158/2767-9764.CRC-21-0137
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