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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 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.

SUBMITTER: Wasko UN

PROVIDER: S-EPMC11111406 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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

Wasko Urszula N UN Jiang Jingjing J Dalton Tanner C TC Curiel-Garcia Alvaro A Edwards A Cole AC Wang Yingyun Y Lee Bianca B Orlen Margo M Tian Sha S Stalnecker Clint A CA Drizyte-Miller Kristina K Menard Marie M Dilly Julien J Sastra Stephen A SA Palermo Carmine F CF Hasselluhn Marie C MC Decker-Farrell Amanda R AR Chang Stephanie S Jiang Lingyan L Wei Xing X Yang Yu C YC Helland Ciara C Courtney Haley H Gindin Yevgeniy Y Muonio Karl K Zhao Ruiping R Kemp Samantha B SB Clendenin Cynthia C Sor Rina R Vostrejs William P WP Hibshman Priya S PS Amparo Amber M AM Hennessey Connor C Rees Matthew G MG Ronan Melissa M MM Roth Jennifer A JA Brodbeck Jens J Tomassoni Lorenzo L Bakir Basil B Socci Nicholas D ND Herring Laura E LE Barker Natalie K NK Wang Junning J Cleary James M JM Wolpin Brian M BM Chabot John A JA Kluger Michael D MD Manji Gulam A GA Tsai Kenneth Y KY Sekulic Miroslav M Lagana Stephen M SM Califano Andrea A Quintana Elsa E Wang Zhengping Z Smith Jacqueline A M JAM Holderfield Matthew M Wildes David D Lowe Scott W SW Badgley Michael A MA Aguirre Andrew J AJ Vonderheide Robert H RH Stanger Ben Z BZ Baslan Timour T Der Channing J CJ Singh Mallika M Olive Kenneth P KP

Nature 20240408 8013

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 R ...[more]

PMID: 38588697

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Project description:BackgroundPancreatic Ductal Adenocarcinoma (PDAC) is an aggressive and lethal disease, lacking effective therapeutic approaches. Available therapies only marginally prolong patient survival and are frequently coupled with severe adverse events. It is therefore pivotal to investigate novel and safe pharmacological approaches. We have recently identified the ABC transporter, ABCC3, whose expression is dependent on mutation of TP53, as a novel target in PDAC. ABCC3-mediated regulation of PDAC cell proliferation and tumour growth in vivo was demonstrated and was shown to be conferred by upregulation of STAT3 signalling and regulation of apoptosis.MethodsTo verify the potential of ABCC3 as a pharmacological target, a small molecule inhibitor of ABCC3, referred to here as MCI-715, was designed. In vitro assays were performed to assess the effects of ABCC3 inhibition on anchorage-dependent and anchorage-independent PDAC cell growth. The impact of ABCC3 inhibition on specific signalling pathways was verified by Western blotting. The potential of targeting ABCC3 with MCI-715 to counteract PDAC progression was additionally tested in several animal models of PDAC, including xenograft mouse models and transgenic mouse model of PDAC.ResultsUsing both mouse models and human cell lines of PDAC, we show that the pharmacological inhibition of ABCC3 significantly decreased PDAC cell proliferation and clonal expansion in vitro and in vivo, remarkably slowing tumour growth in mice xenografts and patient-derived xenografts and increasing the survival rate in a transgenic mouse model. Furthermore, we show that stromal cells in pancreatic tumours, which actively participate in PDAC progression, are enriched for ABCC3, and that its inhibition may contribute to stroma reprogramming.ConclusionsOur results indicate that ABCC3 inhibition with MCI-715 demonstrated strong antitumor activity and is well tolerated, which leads us to conclude that ABCC3 inhibition is a novel and promising therapeutic strategy for a considerable cohort of patients with pancreatic cancer.

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

Publications

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

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