Enhanced MET Translation and Signaling Sustains K-Ras–Driven Proliferation under Anchorage-Independent Growth Conditions

Abstract

Oncogenic K-Ras mutation occurs frequently in several types of cancers including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global down-regulation of mRNA translation during anchorage independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras mediated Met expression drives “K-Ras addiction” in anchorage independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients.

Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

“…4B , left). Despite the lack of growth inhibition in some lines, we found that ARS-853 effectively inhibited RAF-RBD KRAS dependence is well established to be more pronounced in 3-D and/or anchorage-independent settings than in adherent growth assays (10)(11)(12). In line with gene-targeted approaches (10)(11)(12), all tested KRAS G12C cell lines were robustly inhibited by ARS-853 in soft-agar colony formation assays with an average ∼ 2 μ mol/L IC 50 ( Fig.…”

Genomic Status ofMETPotentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors

“…In an esophagogastric cancer patient treated with a MET inhibitor, a KRAS mutation was discovered as a novel cause of acquired resistance (50). Whereas in KRAS-addicted cancer cells, KRAS mediated MET expression via increased MET translation and promoted “KRas addiction” in anchorage-independent conditions (51). Given the pleiotropic effects of MET activation (10) and its emerging role in therapy resistance (52,53), these data provide strong rationale for further exploration of MET-RAS and RAS-MET signal interactions in NF1-related MPNSTs.…”

Genetics and biology of pancreatic ductal adenocarcinoma

“…This mutation is a key initiator, as evidenced by its presence in PanIN lesions (Kanda et al 2012;Murphy et al 2013) and the production of PanIN lesions in oncogenic Kras-driven GEMMs (Hezel et al 2006;Perez-Mancera et al 2012a). While some PDAC cell lines in two-dimensional (2D) culture can tolerate shRNA-mediated KRAS extinction (Singh et al 2009), most PDAC cells remain highly addicted to oncogenic KRAS for tumor maintenance in three-dimensional (3D) culture (Zhang et al 2006;Fujita-Sato et al 2015) and inducible oncogenic Kras GEMMs with advanced tumors (Collins et al 2012;Ying et al 2012). These data strongly support the view that KRAS is a prime therapeutic target for PDAC.…”