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

Urszula N Wasko^1,2, Jingjing Jiang³, Tanner C Dalton^1,2

¹Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

|April 8, 2024

Abstract:

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations^1,2. 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.

Insights

Broad-spectrum RAS inhibition with RMC-7977 shows significant anti-tumor activity in pancreatic ductal adenocarcinoma models. Combination therapy may overcome resistance mechanisms, offering a promising treatment strategy.

Area of Science:

Oncology
Molecular Biology
Drug Discovery

Background:

RAS mutations drive approximately a quarter of human cancers.
Pancreatic ductal adenocarcinoma (PDAC) is frequently driven by KRAS mutations (>90%).
Targeting RAS offers a potential therapeutic strategy for various cancers.

Purpose of the Study:

To assess the therapeutic potential of RMC-7977, a selective RAS-GTP inhibitor, in preclinical models of PDAC.
To investigate the anti-tumour activity and tolerability of RMC-7977 in PDAC.
To identify resistance mechanisms and potential combination therapies.

Main Methods:

In vitro and in vivo evaluation of RMC-7977 in diverse PDAC models.
Pharmacological analysis of drug effects on tumour and normal tissues.
Assessment of survival extension and resistance mechanisms in the KPC mouse model.
In vitro testing of combinatorial TEAD inhibition to overcome resistance.

Main Results:

RMC-7977 demonstrated broad and potent anti-tumour activity across PDAC models with good in vivo tolerability.
Tumours exhibited apoptosis and sustained proliferative arrest, while normal tissues showed transient effects without apoptosis.
RMC-7977 treatment significantly extended survival in the KPC mouse model, followed by relapse.
Myc copy number gain was identified as a resistance mechanism, responsive to combinatorial TEAD inhibition.

Conclusions:

Broad-spectrum RAS-GTP inhibition is a promising strategy for PDAC treatment.
RMC-7977 exhibits significant preclinical anti-tumour efficacy in PDAC models.
Combinatorial inhibition of TEAD presents a viable strategy to overcome RMC-7977 resistance.

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