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

Robert E. Van Sciver, Michael P. Lee, Caroline Dasom Lee, Alex C. Lafever, Elizaveta Svyatova, Kevin Kanda, Amber L. Colliver, 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, Amy H. Tang

Research output: Contribution to journalReview article

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number142
JournalCancers
Volume10
Issue number5
DOIs
StatePublished - May 1 2018

    Fingerprint

Keywords

  • Evolutionary conservation
  • Oncogenic K-RAS mutations
  • Oncogenic K-RAS pathway activation
  • Oncogenic K-RAS-driven tumor relapse and metastasis
  • Pancreatic tumor vulnerability
  • Signaling gatekeeper
  • SINA and SIAH family of RING domain E3 ligases
  • Ubiquitin-mediated proteolysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Van Sciver, R. E., Lee, M. P., Lee, C. D., Lafever, A. C., Svyatova, E., Kanda, K., Colliver, 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. (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(5), [142]. https://doi.org/10.3390/cancers10050142