PRMT5 plus pan-RAS combo enters clinic with no data against proven RAS survival bar

Tango and Erasca Initiate Phase 1/2 Study for Vopimetostat and ERAS-0015 Combination

Tango Therapeutics and Erasca have announced the initiation of a Phase 1/2 open-label, multicenter study for their oral PRMT5 inhibitor, vopimetostat, in combination with the pan-RAS molecular glue, ERAS-0015. This study is enrolling patients with MTAP-deleted pancreatic ductal adenocarcinoma (PDAC) and MTAP-deleted/RAS-mutant non-small cell lung cancer (NSCLC). The primary objective of the dose-escalation portion is to determine the maximum tolerated dose of the combination, with secondary objectives including assessment of antitumor activity, pharmacokinetics, safety, and tolerability. This collaboration aims to explore the synergistic potential of co-targeting PRMT5 and RAS pathways in these difficult-to-treat cancers.

• Strategic Combination Therapy: The Phase 1/2 study evaluates vopimetostat, an investigational PRMT5 inhibitor, in combination with ERAS-0015, a pan-RAS molecular glue. This dual-targeted approach is designed to create a complementary inhibition of both PRMT5 and RAS pathways, aiming for deeper and more durable responses in patients with MTAP-deleted and RAS-mutant cancers.
• Targeted Patient Population: The trial specifically targets patients with MTAP-deleted pancreatic ductal adenocarcinoma (PDAC) and MTAP-deleted/RAS-mutant non-small cell lung cancer (NSCLC). This focus leverages the understanding of genetic vulnerabilities in these cancers, where MTAP deletion is associated with PRMT5 inhibition sensitivity and RAS mutations drive cancer growth.
• Clinical Rationale and Prior Data: The initiation is supported by encouraging clinical activity, durability, and tolerability observed with vopimetostat in combination with RAS inhibition in previous studies. ERAS-0015 has also shown favorable safety, tolerability, and confirmed/unconfirmed partial responses in its AURORAS-1 Phase 1 trial, reinforcing the potential synergy of this combination.

The Unmet Need in MTAP-Deleted Pancreatic and Lung Cancers

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge with dismal long-term outcomes, and fewer than 15% of pancreatic cancer patients survive 5 years. Approximately ~22% of PDAC are MTAP-del, frequently occurring as CDKN2A/MTAP co-deletion, underscoring the need for more effective therapies.

• Dismal prognosis and limited durable options: PDAC contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer, with 5-year survival consistently below 10% and only modest gains from conventional chemotherapy after first-line failure.

• Resistance limits PRMT5 inhibitor efficacy: Next-generation protein arginine methyltransferase 5 (PRMT5) inhibitors show promising clinical results in a subset of PDACs with co-deletion of CDKN2A and MTAP, but resistance limits their efficacy, with compensatory spliceosomal reprogramming and upregulation of RNA-binding proteins, including RNA-binding protein 39 (RBM39), contributing to adaptation to PRMT5 inhibition.

• Single-agent activity is insufficient and combinations are required: Effective cancer treatment typically requires therapeutic combinations to improve response rates and defeat emergent resistant clones, and strategies to maximize therapeutic efficacy of PRMT5 inhibitors remain undefined; KRAS inhibitors have demonstrated initial signs of clinical efficacy but considering currently documented response rates and resistance development, additional targeted therapies are needed.

• Toxicity of earlier PRMT5 inhibitors: The MTA-cooperative PRMT5 inhibitor BMS-986504 demonstrated activity in MTAP-del patients without the toxicity associated with previous PRMT5 inhibitors, highlighting toxicity as a limitation of earlier agents.

Co-Targeting PRMT5 and Pan-RAS: A Synergistic Approach

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in MTAP-deleted (MTAP-del) cancers, with approximately 22% of pancreatic ductal adenocarcinoma (PDAC) reported as MTAP-del. The MTA-cooperative PRMT5 inhibitor BMS-986504 suppressed PRMT5 function and cell growth in MTAP-del cells and xenograft models, and CRISPR/Cas9 loss-of-function screens implicated co-targeting KRAS as a combination strategy. Concurrent inhibition of PRMT5 and KRASG12C/D enhanced and prolonged suppression of PDAC growth. PRMT5 inhibition disrupted RNA splicing of genes essential for PDAC growth, and while PRMT5 and KRAS regulated distinct transcriptomes, they converged on pathways governing cancer cell growth and expression of PDAC-essential genes. In parallel, paralog and single gene targeting CRISPR screening showed loss of several genes, including members of the MAPK pathway, sensitized to PRMT5 inhibition, with chemical inhibition using KRAS, MEK, ERK, and RAF inhibitors synergizing with PRMT5 inhibition to kill CDKN2A/MTAP-null, RAS-active tumors. MTA-cooperative PRMT5 inhibitors combined with either KRAS or RAF inhibitors led to complete responses in vivo, and cell lines resistant to KRAS inhibition were not resistant to MTA-cooperative PRMT5 inhibitors and vice versa, suggesting non-cross-reactive mechanisms of resistance.

A second axis of investigation exploits PRMT5 inhibition-induced defects in DNA damage response. Pharmacologic inhibition of PRMT5 markedly reduces ATM levels across multiple PDAC cell lines, resulting in a functional ATM-deficient state that rewires signaling and increases reliance on the ATR-CHK1 pathway for survival. Combined PRMT5 and CHK1 inhibition showed synergistic suppression of PDAC growth, accompanied by enhanced Caspase 3/7 activation, Annexin V staining, and DNA damage accumulation, with RNA-seq demonstrating downregulation of cell-cycle and DNA repair genes along with upregulation of cell death pathways. In subcutaneous xenografts, the combination substantially reduced tumor volume, prolonged median survival, and did not adversely affect body weight, with treated tumors showing reduced ATM and Ki67 with elevated γH2A.X. Separately, in vivo CRISPR screening in an orthotopic patient-derived xenograft model identified PRMT5 as a synthetic lethality combinatorial target with gemcitabine, where genetic depletion and pharmacologic inhibition showed loss of PRMT5 activity synergistically enhances gemcitabine cytotoxicity due to accumulation of excessive DNA damage, RPA depletion and impaired homology-directed DNA repair activity, creating conditional lethality and synergistic reduction of PDAC tumors in vivo.

A third approach targets adaptive spliceosomal reprogramming following PRMT5 inhibition. Comprehensive molecular profiling demonstrated that PRMT5 inhibitors induce upregulation of RNA-binding proteins, including RNA-binding protein 39 (RBM39). Combining PRMT5 inhibition with indisulam-mediated RBM39 degradation yielded synergistic activity in cellular model systems, significantly enhanced apoptotic cell death and suppressed tumor outgrowth in resistance assays compared to single-agent treatments. Multi-omics analysis revealed concomitant suppression of DNA repair and metabolic pathways, supporting spliceosomal rewiring as a candidate adaptive response and nominating RBM39 as a candidate therapeutic vulnerability for dual targeting of the splicing machinery.