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

Abstract

KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRAS G12C that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specifi c mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRAS G12C is in a state of dynamic fl ux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS G12C mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics. SIGNIFICANCE:A cell-active, mutant-specifi c, covalent inhibitor of KRAS G12C is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compound, we demonstrate that KRAS G12C oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state. Cancer Discov; 6(3); 316-29.

Reverse engineering GTPase programming languages with reconstituted signaling networks

“…10,13,14 More recently, the Ras G12C was shown to actively cycle in a "hyper-excitable" state in cells, illustrating that some undesirable features of oncogenic alleles may only be manifest in a cycling network context. 15 In agreement with this, we found that the network context was critical for revealing differences between oncogenic and wildtype alleles of Ras (Fig. 3).…”

KRAS mutations in the circulating free DNA (cfDNA) of non-small cell lung cancer (NSCLC) patients

“…Further research is required to understand KRAS mutations and to develop drugs targeted against them (6). Some recent investigations have generated a renewed interest in the development of direct KRAS inhibitors (19). For instance, Lito and colleagues (20) achieved blockade of nucleotide exchange factors from activating KRAS.…”

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

“…More recent work has connected increased glucose metabolism to oncogene activation (12), setting the stage for numerous studies detailing the role of oncogenes and tumor suppressors in regulating cancer cell metabolism to promote the accumulation of biomass necessary for enhanced proliferation (13)(14)(15). Because drugs are lacking to specifically treat patients with tumors harboring many mutations in genes such KRAS and TP53, one hope is to identify other pathway dependencies in these cancers (16)(17)(18). Both KRAS and TP53 mutations result in metabolic changes, and efforts to target the downstream metabolic effects of these events have demonstrated preclinical potential and led to development of drugs in current clinical trials (19,20).…”