Dasatinib demonstrates efficacy in organoid derived paclitaxel-resistant Trp53/Cdh1-deficient mouse gastric adenocarcinoma with peritoneal metastasis.

Abstract

Gastric cancer peritoneal metastasis (GCPM) typically indicates a poor clinical prognosis and is frequently observed in diffuse gastric cancer (GC) patients with CDH1 loss of function. GCPM characterized for its aggressiveness and resistance to chemotherapy, most notably paclitaxel (PTX), poses significant treatment challenges. Previously, no mouse gastric adenocarcinoma (MGA) cell lines with Trp53 (encoding mouse p53) and Cdh1 (encoding mouse E-cadherin) mutations and a high potential for peritoneal metastasis in mice have been established. Here, we derived a mouse GC cell line, called MTC, from subcutaneously transplanted mouse Trp53^-/-Cdh1^-/- GC organoids. Through matching the short tandem repeat profile of MTC with those in current cell banks, we verified the uniqueness of MTC. Furtherly, we confirmed the features of MTC by detecting the expression of p53, E-cadherin, and pan-CK. After long-term exposure of the original MTC line to PTX, we developed a more aggressive, PTX-resistant cell line, termed MTC-R. Compared with MTC, MTC-R demonstrated enhanced tumorigenicity and high potential for peritoneal metastasis in subcutaneous and intraperitoneal tumour models both in BALB/c nude mice and C57BL/6 J mice. Transcriptome analysis revealed the ECM‒receptor interaction pathway activation during the development of PTX resistance, and dasatinib (DASA) was identified as a potential drug targeting this pathway. DASA showed promise in ameliorating disease progression and improving overall survival in MTC-R GCPM model in C57BL/6 J mice. Overall, we established a novel MGA cell line with Trp53 and Cdh1 mutations and its PTX-resistant variant and demonstrated the efficacy of DASA in treating PTX-resistant GCPM.