Targeting Oncomucin-Driven Immunosuppression Improves the Efficacy of K-ras<sup>G12D</sup> Inhibition in Pancreatic Cancer.

Abstract

Oncogenic de novo mucins (oncoMUCs; MUC4, MUC16, and MUC5AC) are progressively upregulated in pancreatic ductal adenocarcinoma (PDA). Although their individual cell-intrinsic roles have been investigated, their collective impact on PDA progression and the tumor microenvironment (TME) remains unclear. Evaluating the patient-centric impact of oncoMUCs on the TME will inform diagnostic and therapeutic strategies.

Integration of single-cell RNA sequencing (n = 34), multiplex/sequential immunostaining, and murine models characterized the oncomucinome. Immune suppression was investigated using NanoString profiling and gene silencing. Pharmacologic oncoMUC targeting (Istradefylline) was evaluated in combination with K-ras<sup>G12D</sup> inhibitor in a syngeneic murine model.

OncoMUCs showed extensive clonal diversity and survival disadvantage (P = .00013) in PDA. OncoMUC4 and oncoMUC16 subpopulations were enriched after stage IIA/B, and their deletion significantly reduced immune checkpoints (ICs) expression (V-domain immunoglobulin suppressor of T-cell activation [VISTA]: P < .0001, .001; T-cell immunoglobulin and mucin domain-containing protein 3 [TIM3]: P < .0001, .001), and increased CD8<sup>+</sup> T-cell (P = .0087) and antigen-presenting cell infiltration (macrophages: P < .004; dendritic cells: P = .021) in tumors of PDA autochthonous models. Mechanistically, these subpopulations potentiate epidermal growth factor receptor (EGFR) and Unc-5 Netrin Receptor B (UNC5B) signaling, which collaboratively upregulate ICs, VISTA, and programmed death ligand 1 ([PD-L1] P < .0001). As Kras<sup>G12D</sup> inhibition (MRTX1133) upregulated oncoMuc4 and oncoMuc16 expression, pharmacological targeting of oncoMUCs enhanced the efficacy of MRTX1133, as indicated by reduced tumor burden (P = .034), ICs (local, [P range 0.03-0.009] and systemic VISTA and TIM3 [P = .024, .014]), and Unc5b (P = .048) expression.

Transmembrane oncoMUCs promote immune evasion in PDA through EGFR/UNC5B signaling, and their targeting enhances the efficacy of K-ras<sup>G12D</sup> inhibition, suggesting oncoMUCs as novel immune regulators and therapeutic targets in PDA.

EDRN PI Authors
Medline Author List
  • Aithal A
  • Alsafwani ZW
  • Atri P
  • Batra SK
  • Bhyravbhatla N
  • Centeno BA
  • Cox JL
  • Ghersi D
  • Khan I
  • Kumar S
  • Malafa M
  • Marimuthu S
  • Moran Segura CM
  • Nallasamy P
  • Park MA
  • Thapa I
  • Villalobos-Ayala K
PubMed ID
42191046
Sources
  • Cancer Data Expo
Appears In
Gastroenterology, 2026 Oct (issue 4)