# The Therapeutic Role of NPS-1034 in Pancreatic Ductal Adenocarcinoma as Monotherapy and in Combination with Chemotherapy

## TL;DR

NPS-1034, a drug targeting MET and AXL kinases, shows promise in treating pancreatic cancer alone or with chemotherapy by reducing cancer cell growth and enhancing immune responses.

## Contribution

NPS-1034 demonstrates monotherapy and synergistic chemotherapeutic efficacy in PDAC by modulating cell death, migration, and immune responses.

## Key findings

- NPS-1034 reduces PDAC cell viability, clonogenicity, and migration by inhibiting MET/PI3K/AKT signaling and EMT.
- Combining NPS-1034 with fluorouracil or oxaliplatin synergistically reduces cell viability and induces apoptosis.
- NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells.

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in terms of diagnosis and treatment, with limited therapeutic options and a poor prognosis. This study explored the potential therapeutic role of NPS-1034, a kinase inhibitor targeting MET and AXL, in PDAC. The investigation included monotherapy with NPS-1034 and its combination with the commonly prescribed chemotherapy agents, fluorouracil and oxaliplatin. Our study revealed that NPS-1034 induces cell death and reduces the viability and clonogenicity of PDAC cells in a dose-dependent manner. Furthermore, NPS-1034 inhibits the migration of PDAC cells by suppressing MET/PI3K/AKT axis-induced epithelial-to-mesenchymal transition (EMT). The combination of NPS-1034 with fluorouracil or oxaliplatin demonstrated a synergistic effect, significantly reducing cell viability and inducing tumor cell apoptosis compared to monotherapies. Mechanistic insights provided by next-generation sequencing indicated that NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells. This suggests a broader role for NPS-1034 beyond MET and AXL inhibition, positioning it as a potential immunity modulator. Overall, these findings highlight the anticancer potential of NPS-1034 in PDAC treatment in vitro, both as a monotherapy and in combination with traditional chemotherapy, offering a promising avenue for further in vivo investigation before clinical exploration.