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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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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. |
format | Online Article Text |
id | pubmed-5977115 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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