Dynamic phospho-proteogenomic analysis of gastric cancer cells suggests host immunity provides survival benefit
Kume, K.; Iida, M.; Iwaya, T.; Yashima-Abo, A.; Koizumi, Y.; Konta, A.; Wade, K.; Hiraki, H.; Calvert, V.; Wulfkuhle, J.; Espina, V.; Siwak, D. R.; Lu, Y.; Takemoto, K.; Suzuki, Y.; Sasaki, Y.; Tokino, T.; Petricoin, E.; Liotta, L. A.; Mills, G. B.; Nishizuka., S. S.
Show abstract
The mainstay of advanced gastric cancer (GC) therapy is DNA-damaging drugs. Using proteogenomic analysis of a panel of eight GC cell lines, we identified genetic alterations and signaling pathways, potentially associated with resistance to DNA-damaging drugs. Notably, 5-fluorouracil (5FU) resistance was associated with PD-L1 expression, but not established GC subtypes. In publicly available cohort data, PD-L1 expression was associated with a reduced risk of GC progression. In addition to PD-L1, expression of inflammatory genes induced by lymphocyte cytokines was consistently associated with prolonged survival in GC. In our validation cohort, total lymphocyte count (TLC) predicted a better relapse-free survival rate in GC patients with 5FU-based adjuvant chemotherapy than those with surgery alone. Moreover, TLC+ patients who had no survival benefit from adjuvant chemotherapy were discriminated by I{kappa}B expression. Collectively, our results suggest that 5FU resistance observed in cell lines may be overcome by host immunity or by combination therapy with immune checkpoint blockade.
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