SRC-homology 2 domain-containing phosphatase 2 (SHP2) in resected epidermal growth factor receptor mutation-positive lung adenocarcinoma

Abstract Introduction Epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of extracellular signal-regulated kinase (ERK) and SRC-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. We hypothesize that SHP2 expression could be predictive in resected EGFR mutation-positive versus EGFR wild-type LUAD patients. Methods We examined resected lung adenocarcinoma cases from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1 and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction (PCR). The activity of SHP2 inhibitors plus erlotinib were tested in EGFR-mutant cell lines and analyzed by cell viability assay, western blot and immunofluorescence. Results Fifty of 100 EGFR mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression demonstrated shorter progression free survival, in comparison with those having low SHP2 mRNA (hazard ratio, 1.83; 95% CI, 1,05 to 3.23; P=0.0329). However, SHP2 was not associated with prognosis in the remaining 167 wild-type EGFR patients. In EGFR-mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib demonstrated synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). While erlotinib translocates phosphorylated SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocates SHP2 into the cytoplasm membrane, limiting AKT and ERK 1/2 activation. Conclusions Elevated SHP2 mRNA levels are associated with recurrence in resected EGFR mutation-positive LUADs, but not in EGFR wild-type. EGFR tyrosine kinase inhibitors (TKIs) can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in EGFR mutation-positive LUADs.