Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

Abstract

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC

“…Adaptive K-Ras inhibitor resistance is accompanied by significant metabolic reprogramming of cancer cells, including hyperactivation of the PI3K/AKT pathway 17,18 , elevated TCA cycle flux 19 , Myc amplification 20 , and upregulation of mitochondrial biogenesis 21 , culminating in heightened reliance on oxidative phosphorylation (OXPHOS). 21,22 As K-Ras pathway inhibition impairs glycolysis, forcing cancer cells to rely on OXPHOS for their energetic demands, this mechanism of clinical resistance is expected to impact the entire pharmacological class and is already being reported in laboratory studies of other K-Ras mutant targeting drug candidates.…”

“…We recently demonstrated that acquired resistance to the K-Ras G12D inhibitor MRTX1133 in human PDAC cells is associated with feedback activation of ERBB/AKT signaling and enhanced OXPHOS. 14 Resistance to the mechanistically orthogonal pan K-Ras(ON) inhibitor RM-7977 has been recently reported in murine models of PDAC, and is associated with Myc amplification 20 . While metabolic profiling was not performed in this study, Myc overexpression has been shown to result in increased mitochondrial biogenesis 23 , and over 200 OXPHOS genes are regulated by Myc.…”