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

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.

The phylogenetic functional conservation ofDrosophilaSeven-In-Absentia (SINA) E3 ligase and its two human paralogs, SIAH1 and SIAH2, inDrosophilaeye development

“…Our phylogenetic analysis showed that each of these cysteine residues (C104Y, C73Y, and/or C76Y) corresponded to an invariable cysteine that is responsible for zinc-coordination in the RING domain of SINA E3 ligase. Our results indicated the critical cysteine residues are required for proper SINA function in relaying RAS signal in Drosophila eye development (Figure 1) [31,32]. A majority of 28 newly isolated sina mutant alleles are embryonic lethal, resembling that of a large sina deletion allele, sina DF(81K72) [33].…”

“…Thus, a large collection of 28 newly identified Our sequencing data revealed point mutations resulting in C104Y, C73Y, or C76Y substitutions in sina ES10 , sina ES79 , or sina ES473 , respectively, and a 10 base pair deletion in sina ES26 (Figure 1A and Table 1). The three C to Y amino acid substitutions mutated the invariable cysteine (Cys) amino acids that are responsible for zinc coordination in the RING domain of SINA [31,32] ( Figure 1A). Without proper SINA function, activation of upstream RAS/RAF/MAPK signals (e.g.…”

“…Drosophila SINA and human SIAH1/2 are functionally conserved in Drosophila eye development Supported by a high degree of amino acid identity and cross-species protein sequence conservation in metazoan SINA/SIAH proteins, we hypothesized that human SIAHs are likely to play a similar gatekeeper function as Drosophila SINA by serving as the key downstream signaling hub essential for active K-RAS signal transduction [28][29][30]32]. To test this hypothesis, we examined the functional conservation of Drosophila SINA and human SIAH1/2 in vivo.…”

“…This elegant system was instrumental in identifying the key signaling components and elucidating the conserved operational principles of the RAS signal transduction cascade in vivo [24][25][26][27][28]. Due to the extraordinary degree of evolutionary conservation of RAS signaling pathway in metazoans, the molecular insights and core principles learned from Drosophila RAS studies have informed and guided many aspects of mammalian K-RAS studies in human cancer [28][29][30][31][32]. Seven-IN-Absentia (SINA) is an evolutionarily conserved RING-domain E3 ubiquitin ligase that serves as the most downstream signaling hub whose function is indispensable for proper RAS signal transduction [25,31,33,34].…”

“…Guided by ample evidence in developmental, evolutionary, and cancer biology, we proposed an alternative strategy to shutdown "undruggable" oncogenic K-RAS activation by targeting human SINA homologs (SIAHs) in human cancer cells [28][29][30][31][32]34]. Using a proteolytic deficient (PD) SIAH mutant to block SIAH1/2 function, we demonstrated that human SIAHs are a major tumor vulnerability of oncogenic K-RAS/EGFR-driven tumorigenesis and metastasis in human pancreatic and lung cancer [29,30] (triple negative breast cancer data not shown).…”