Src-Homology 2 Domain-Containing Phosphatase 2 in Resected Mutation-Positive Lung Adenocarcinoma.

INTRODUCTION

mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected mutation versus patients with wild-type LUAD.

METHODS

We examined resected LUAD cases from Japan and Spain. mRNA expression levels of , , , , , and were analyzed by quantitative reverse transcriptase polymerase chain reaction. The activity of SHP2 inhibitors plus erlotinib were tested in -mutant cell lines and analyzed by cell viability assay, Western blot, and immunofluorescence.

RESULTS

A total of 50 of 100 mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression revealed shorter progression-free survival, in comparison with those having low SHP2 mRNA (hazard ratio: 1.83; 95% confidence interval: 1.05-3.23;  = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type . In -mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib revealed synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). Although 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 ERK1/2 activation.

CONCLUSIONS

Elevated mRNA levels are associated with recurrence in resected mutation-positive LUADs, but not in wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in mutation-positive LUADs.