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Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma

ABSTRACT: Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. 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 (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient-derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Pancreatic Ductal Adenocarcinoma

SUBMITTER: Clint Stalnecker

LAB HEAD: Channing Der

PROVIDER: PXD047878 | Pride | 2024-03-15

REPOSITORIES: Pride

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Publications

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.

Wasko Urszula N UN Jiang Jingjing J Curiel-Garcia Alvaro A Wang Yingyun Y Lee Bianca B Orlen Margo M Drizyte-Miller Kristina K Menard Marie M Dilly Julien J Sastra Stephen A SA Palermo Carmine F CF Dalton Tanner T 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 Zhao Ruiping R Kemp Samantha B SB Clendenin Cynthia C Sor Rina R Vostrejs Will W Amparo Amber A AA Hibshman Priya S PS Rees Matthew G MG Ronan Melissa M MM Roth Jennifer A JA Bakir Basil B Badgley Michael A MA Chabot John A JA Kluger Michael D MD Manji Gulam A GA Quintana Elsa E Wang Zhengping Z Smith Jacqueline A M JAM Holderfield Matthew M Wildes David D Aguirre Andrew J AJ Der Channing J CJ Vonderheide Robert H RH Stanger Ben Z BZ Singh Mallika M Olive Kenneth P KP

bioRxiv : the preprint server for biology 20231204

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. 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 (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in <i>KRAS</i>, we ...[more]

PMID: 38105998

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Familial predisposition to PDAC occurs in ~10% of cases, but causative genes have not been identified in most families. Uncovering the genetic basis for PDAC susceptibility has immediate prognostic implications for families and can provide mechanistic clues to PDAC pathogenesis. Here, we perform whole-genome sequence analysis in a family with multiple cases of PDAC and identify a germline nonsense mutation in the member of RAS oncogene family-like 3 (RABL3) gene never before directly associated with hereditary cancer. The truncated mutant allele (RABL3_p.S36*) co-segregates with cancer occurrence. To evaluate the contribution of the RABL3 mutant allele in hereditary cancer, we generated rabl3 heterozygous mutant zebrafish and found increased susceptibility to cancer formation in two independent cancer models. Unbiased approaches implicate RABL3 in RAS pathway regulation: the transcriptome of juvenile rabl3 mutants reveals a KRAS upregulation signature, and affinity-purification mass spectrometry for proteins associated with RABL3 or RABL3_p.S36* identifies Rap1 GTPase-GDP Dissociation Stimulator 1 (RAP1GDS1, SmgGDS), a chaperone that regulates prenylation of RAS GTPases. Indeed, we find that RABL3_p.S36* accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Furthermore, rabl3 homozygous mutant zebrafish develop severe craniofacial, skeletal, and growth defects consistent with human RASopathies, and these defects are partially rescued with the MEK inhibitor trametinib. Finally, we identify additional germline mutations in RABL3 that impact RAS activity in vivo and have a significant burden in a cohort of patients with developmental disorders, suggesting a role in undiagnosed RASopathies. Moreover, RABL3 is upregulated in multiple human PDAC cell lines and knockdown abrogates proliferation, consistent with a broader role for RABL3 in PDAC. Our studies identify the RABL3 mutation as a new target for genetic testing in cancer families and uncover a novel mechanism for dysregulated RAS activity in development and cancer.

Dataset Information

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma

Publications

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.

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