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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

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Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, USA
2
School of Medicine, Eastern Virginia Medical School, Norfolk, VA 23507, USA
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Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA
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Department of Surgery, Eastern Virginia Medical School, Norfolk, VA 23507, USA
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Department of Biology, Upper Iowa University, Fayette, IA 52142, USA
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Pancreatic Cancer Action Network, 1500 Rosecrans Ave, Suite 200, Manhattan Beach, CA 90266, USA
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Department of Health Sciences Research, Mayo Clinic Cancer Center, Mayo Clinic Pancreatic Cancer SPORE, BioBusiness 5-85, 200 First Street SW, Rochester, MN 55905, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2018, 10(5), 142; https://doi.org/10.3390/cancers10050142
Received: 29 January 2018 / Revised: 8 May 2018 / Accepted: 10 May 2018 / Published: 14 May 2018
(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)
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. View Full-Text
Keywords: oncogenic K-RAS mutations; oncogenic K-RAS pathway activation; SINA and SIAH family of RING domain E3 ligases; evolutionary conservation; ubiquitin-mediated proteolysis; signaling gatekeeper; pancreatic tumor vulnerability; oncogenic K-RAS-driven tumor relapse and metastasis oncogenic K-RAS mutations; oncogenic K-RAS pathway activation; SINA and SIAH family of RING domain E3 ligases; evolutionary conservation; ubiquitin-mediated proteolysis; signaling gatekeeper; pancreatic tumor vulnerability; oncogenic K-RAS-driven tumor relapse and metastasis
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MDPI and ACS Style

Van Sciver, R.E.; Lee, M.P.; Lee, C.D.; Lafever, A.C.; Svyatova, E.; Kanda, K.; Collier, A.L.; Siewertsz van Reesema, L.L.; Tang-Tan, A.M.; Zheleva, V.; Bwayi, M.N.; Bian, M.; Schmidt, R.L.; Matrisian, L.M.; Petersen, G.M.; Tang, A.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. Cancers 2018, 10, 142. https://doi.org/10.3390/cancers10050142

AMA Style

Van Sciver RE, Lee MP, Lee CD, Lafever AC, Svyatova E, Kanda K, Collier AL, Siewertsz van Reesema LL, Tang-Tan AM, Zheleva V, Bwayi MN, Bian M, Schmidt RL, Matrisian LM, Petersen GM, Tang AH. 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. Cancers. 2018; 10(5):142. https://doi.org/10.3390/cancers10050142

Chicago/Turabian Style

Van Sciver, Robert E., Michael P. Lee, Caroline D. Lee, Alex C. Lafever, Elizaveta Svyatova, Kevin Kanda, Amber L. Collier, Lauren L. Siewertsz van Reesema, Angela M. Tang-Tan, Vasilena Zheleva, Monicah N. Bwayi, Minglei Bian, Rebecca L. Schmidt, Lynn M. Matrisian, Gloria M. Petersen, and Amy H. Tang. 2018. "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" Cancers 10, no. 5: 142. https://doi.org/10.3390/cancers10050142

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