Warburg effect and tp53 mutational status in gastric cancer patients under ramucirumab-based therapy

Gastric cancer is one of the most common cancers worldwide and ranks second in cancer-related deaths. To improve the survival rate, several studies have elucidated molecular mechanisms of gastric cancer and identified biomarkers predicting prognosis and response to treatment. Cancer cells exhibit altered glucose metabolism, known as the Warburg effect, characterized by the increased uptake of glucose and rates of aerobic glycolysis even under adequate oxygen levels, leading to lactate accumulation and finally promoting tumor invasion, angiogenesis, immune escape and resistance. Overexpression of key effectors of the Warburg effect, as well as TP53 mutational status, are associated with poor prognosis in cancer but limited data are available in gastric cancer patients under anti-angiogenic therapy. So we have set up two studies: in the first study we investigated whether a positive glycolytic profile in gastric adenocarcinomas might be associated with unfavorable outcomes in patients treated with anticancer systemic therapy, including the anti-angiogenic Ramucirumab. For this purpose, we analyzed the mRNA expression of five key Warburg effect genes, such as GLUT1, HK1, HK2, PKM2 and LDHA in 40 metastatic gastric adenocarcinoma patients under Paclitaxel-Ramucirumab (PR) treatment. We observed that patients with a positive glycolytic profile were related with worse progression-free and overall survival times. In the second study we evaluated the possible predictive impact of TP53 mutations on PR therapy compared to standard chemotherapy. On the basis of the residual transcriptional activity score (RTAS), the TP53 mutations found were classified in TP53active and TP53inactive. Therefore we observed that TP53inactive mutations differentially affect survival outcomes depending on the anti-cancer regimen, in particular PR-treated patients displaying TP53inactive mutations showed a better overall survival respect to patients carrying TP53active mutations. Taken together these findings show that both the glycolytic competence of gastric cancer cells and the TP53inactive mutations may be valuable biomarkers to identify patients with greatest benefit from the anti- angiogenic PR therapy.