# Targeting the c-Met/VEGFR Pathway to Boost Nab-Paclitaxel Efficacy in Gastric Cancer: Preclinical Insights

## TL;DR

Combining merestinib with nab-paclitaxel improves treatment outcomes in gastric cancer by enhancing tumor regression and survival.

## Contribution

The study demonstrates that combining merestinib with nab-paclitaxel is effective in c-Met–high gastric cancer models.

## Key findings

- Combination therapy with merestinib and nab-paclitaxel significantly prolongs survival in high c-Met–expressing gastric cancer models.
- The combination reduces tumor cell proliferation and microvessel density in preclinical models.
- Merestinib enhances the antitumor effects of nab-paclitaxel by modulating oncogenic signaling pathways.

## Abstract

What are the main findings?
Merestinib significantly enhances the antitumor activity of nab-paclitaxel in gastric adenocarcinoma (GAC), particularly in c-Met–high preclinical models.Combination therapy induces tumor regression, prolongs survival, and suppresses tumor cell proliferation, microvessel density, and oncogenic signaling.

Merestinib significantly enhances the antitumor activity of nab-paclitaxel in gastric adenocarcinoma (GAC), particularly in c-Met–high preclinical models.

Combination therapy induces tumor regression, prolongs survival, and suppresses tumor cell proliferation, microvessel density, and oncogenic signaling.

What is the implication of the main finding?
Dual targeting of the HGF/c-Met pathway and microtubule dynamics represents a promising therapeutic strategy for gastric adenocarcinoma.Given the frequent HGF/c-Met overexpression in GAC, this combination may improve treatment outcomes in selected patient populations.

Dual targeting of the HGF/c-Met pathway and microtubule dynamics represents a promising therapeutic strategy for gastric adenocarcinoma.

Given the frequent HGF/c-Met overexpression in GAC, this combination may improve treatment outcomes in selected patient populations.

Combination chemotherapy regimens are commonly employed to treat advanced gastric adenocarcinoma (GAC), yet median survival remains less than one year. Nab-paclitaxel has demonstrated significant antitumor activity in preclinical GAC models. Overexpression of growth factors and their receptors is prevalent in GAC and contributes to its pathophysiology, with aberrant activation of the HGF/c-Met pathway reported in up to 50% of patients. We hypothesized that merestinib, a small-molecule inhibitor of c-Met, Axl, and DDR1/2, would enhance the therapeutic response to nab-paclitaxel in GAC. In high c-Met–expressing MKN-45 peritoneal dissemination xenografts in female NOD/SCID mouse models, animal survival was 17 days in controls, 37 days with nab-paclitaxel (118% increase), 24 days with merestinib (41% increase), and 43 days with the combination (153% increase), demonstrating significantly enhanced survival compared with either monotherapy. In MKN-45 subcutaneous xenografts, tumor volumes in the control, nab-paclitaxel, merestinib, and combination groups were 503 mm3, 115 mm3, 91 mm3, and −9.7 mm3 (indicating tumor regression), respectively. In low c-Met-expressing SNU-1 xenografts, tumor volumes were 219 mm3, 105 mm3, 131 mm3, and 57 mm3, respectively. IHC analysis of tumor cell proliferation and microvessel density in MKN-45 tumors supported these findings. In vitro, nab-paclitaxel and merestinib each reduced cell proliferation in GAC-associated cells, with enhanced inhibitory effects when used in combination. In MKN-45 cells, merestinib increased the expression of pro-apoptotic proteins and decreased phosphorylation of c-Met, EGFR, IGF-1R, ERK, and AKT. These results indicate that combining merestinib with nab-paclitaxel may represent a promising therapeutic strategy to improve outcomes for patients with GAC.