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A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology

Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely “undruggable”. Rather than targetin...

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Autores principales: Van Sciver, Robert E., Lee, Michael P., Lee, Caroline Dasom, Lafever, Alex C., Svyatova, Elizaveta, Kanda, Kevin, Collier, Amber L., Siewertsz van Reesema, Lauren L., Tang-Tan, Angela M., Zheleva, Vasilena, Bwayi, Monicah N., Bian, Minglei, Schmidt, Rebecca L., Matrisian, Lynn M., Petersen, Gloria M., Tang, Amy H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977115/
https://www.ncbi.nlm.nih.gov/pubmed/29757973
http://dx.doi.org/10.3390/cancers10050142
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author Van Sciver, Robert E.
Lee, Michael P.
Lee, Caroline Dasom
Lafever, Alex C.
Svyatova, Elizaveta
Kanda, Kevin
Collier, Amber L.
Siewertsz van Reesema, Lauren L.
Tang-Tan, Angela M.
Zheleva, Vasilena
Bwayi, Monicah N.
Bian, Minglei
Schmidt, Rebecca L.
Matrisian, Lynn M.
Petersen, Gloria M.
Tang, Amy H.
author_facet Van Sciver, Robert E.
Lee, Michael P.
Lee, Caroline Dasom
Lafever, Alex C.
Svyatova, Elizaveta
Kanda, Kevin
Collier, Amber L.
Siewertsz van Reesema, Lauren L.
Tang-Tan, Angela M.
Zheleva, Vasilena
Bwayi, Monicah N.
Bian, Minglei
Schmidt, Rebecca L.
Matrisian, Lynn M.
Petersen, Gloria M.
Tang, Amy H.
author_sort Van Sciver, Robert E.
collection PubMed
description Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely “undruggable”. Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH). SIAH E3 ligase controls the signal output of oncogenic K-RAS hyperactivation that drives unchecked cell proliferation, uncontrolled tumor growth, and rapid cancer cell dissemination in human pancreatic cancer. Therefore, SIAH is an ideal therapeutic target as it is an extraordinarily conserved downstream signaling gatekeeper indispensable for proper RAS signaling. Guided by molecular insights and core principles obtained from developmental and evolutionary biology, we propose an anti-SIAH-centered anti-K-RAS strategy as a logical and alternative anticancer strategy to dampen uncontrolled K-RAS hyperactivation and halt tumor growth and metastasis in pancreatic cancer. The clinical utility of developing SIAH as both a tumor-specific and therapy-responsive biomarker, as well as a viable anti-K-RAS drug target, is logically simple and conceptually innovative. SIAH clearly constitutes a major tumor vulnerability and K-RAS signaling bottleneck in pancreatic ductal adenocarcinoma (PDAC). Given the high degree of evolutionary conservation in the K-RAS/SIAH signaling pathway, an anti-SIAH-based anti-PDAC therapy will synergize with covalent K-RAS inhibitors and direct K-RAS targeted initiatives to control and eradicate pancreatic cancer in the future.
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spelling pubmed-59771152018-05-31 A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology Van Sciver, Robert E. Lee, Michael P. Lee, Caroline Dasom Lafever, Alex C. Svyatova, Elizaveta Kanda, Kevin Collier, Amber L. Siewertsz van Reesema, Lauren L. Tang-Tan, Angela M. Zheleva, Vasilena Bwayi, Monicah N. Bian, Minglei Schmidt, Rebecca L. Matrisian, Lynn M. Petersen, Gloria M. Tang, Amy H. Cancers (Basel) Review Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely “undruggable”. Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH). SIAH E3 ligase controls the signal output of oncogenic K-RAS hyperactivation that drives unchecked cell proliferation, uncontrolled tumor growth, and rapid cancer cell dissemination in human pancreatic cancer. Therefore, SIAH is an ideal therapeutic target as it is an extraordinarily conserved downstream signaling gatekeeper indispensable for proper RAS signaling. Guided by molecular insights and core principles obtained from developmental and evolutionary biology, we propose an anti-SIAH-centered anti-K-RAS strategy as a logical and alternative anticancer strategy to dampen uncontrolled K-RAS hyperactivation and halt tumor growth and metastasis in pancreatic cancer. The clinical utility of developing SIAH as both a tumor-specific and therapy-responsive biomarker, as well as a viable anti-K-RAS drug target, is logically simple and conceptually innovative. SIAH clearly constitutes a major tumor vulnerability and K-RAS signaling bottleneck in pancreatic ductal adenocarcinoma (PDAC). Given the high degree of evolutionary conservation in the K-RAS/SIAH signaling pathway, an anti-SIAH-based anti-PDAC therapy will synergize with covalent K-RAS inhibitors and direct K-RAS targeted initiatives to control and eradicate pancreatic cancer in the future. MDPI 2018-05-14 /pmc/articles/PMC5977115/ /pubmed/29757973 http://dx.doi.org/10.3390/cancers10050142 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Van Sciver, Robert E.
Lee, Michael P.
Lee, Caroline Dasom
Lafever, Alex C.
Svyatova, Elizaveta
Kanda, Kevin
Collier, Amber L.
Siewertsz van Reesema, Lauren L.
Tang-Tan, Angela M.
Zheleva, Vasilena
Bwayi, Monicah N.
Bian, Minglei
Schmidt, Rebecca L.
Matrisian, Lynn M.
Petersen, Gloria M.
Tang, Amy H.
A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology
title A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology
title_full A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology
title_fullStr A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology
title_full_unstemmed A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology
title_short A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology
title_sort new strategy to control and eradicate “undruggable” oncogenic k-ras-driven pancreatic cancer: molecular insights and core principles learned from developmental and evolutionary biology
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977115/
https://www.ncbi.nlm.nih.gov/pubmed/29757973
http://dx.doi.org/10.3390/cancers10050142
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