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Published on: July 17, 2020
Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma
Masaoki Ito1,2,3, Jordi Codony-Servat1, Ana Giménez-Capitán1
1Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, Spain.
Introduction:
EGFR mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of 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 patients positive with resected EGFR mutation versus patients with EGFR wild-type LUAD.
Methods:
We examined resected LUAD 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. 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:
A total of 50 of 100 EGFR 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; p = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type EGFR. In EGFR-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 SHP2 mRNA levels are associated with recurrence in resected EGFR mutation-positive LUADs, but not in EGFR wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in EGFR mutation-positive LUADs.
Insights
Elevated Src-homology 2 domain-containing phosphatase 2 (SHP2) mRNA levels predict recurrence in EGFR mutation-positive lung adenocarcinoma. SHP2 inhibitors may enhance adjuvant therapy effectiveness in these patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- EGFR mutation-positive lung adenocarcinoma (LUAD) exhibits distinct signaling impairments compared to wild-type LUAD.
- Src-homology 2 domain-containing phosphatase 2 (SHP2) activity is implicated in EGFR signaling pathways.
- The predictive role of SHP2 expression in resected LUAD requires further investigation.
Purpose of the Study:
- To investigate the association between SHP2 mRNA expression and prognosis in resected EGFR mutation-positive LUAD.
- To evaluate the efficacy of SHP2 inhibitors in combination with erlotinib in EGFR-mutant LUAD cell lines.
- To elucidate the molecular mechanisms underlying the response to combined SHP2 inhibition and erlotinib therapy.
Main Methods:
- Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to analyze mRNA expression levels of SHP2 and other relevant genes in resected LUAD tissues from Japan and Spain.
- SHP2 inhibitors (SHP099, RMC-4550) combined with erlotinib were tested in EGFR-mutant LUAD cell lines.
- Cell viability assays, Western blotting, and immunofluorescence were employed to assess treatment efficacy and molecular changes.
Main Results:
- Higher SHP2 mRNA expression was significantly associated with shorter progression-free survival in EGFR mutation-positive LUAD patients (HR: 1.83, p=0.0329).
- SHP2 expression did not correlate with prognosis in EGFR wild-type LUAD patients.
- Combination therapy with SHP2 inhibitors and erlotinib demonstrated synergistic effects, abrogating phosphorylated AKT and ERK1/2, and altering SHP2 subcellular localization.
Conclusions:
- Elevated SHP2 mRNA levels are a predictive marker for recurrence in resected EGFR mutation-positive LUAD.
- EGFR tyrosine kinase inhibitors can paradoxically enhance SHP2 activation, potentially limiting adjuvant therapy efficacy.
- SHP2 inhibitors hold promise for improving the efficacy of adjuvant therapy in EGFR mutation-positive LUAD.
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