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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma
Jie Xu1, Li-Fan Zeng, Weihua Shen
1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States.
Abstract:
Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g. T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, we observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.
Insights
Targeting SHP2 offers a new strategy for non-small cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) inhibitors. SHP2 inhibition reduced tumor growth and signaling, showing promise for treating resistant NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) inhibitors benefit non-small cell lung cancer (NSCLC) patients with activating EGFR mutations.
- Acquired resistance to EGFR inhibitors, often due to secondary EGFR mutations like T790M, limits treatment efficacy.
- SHP2 phosphatase plays a key role in growth factor receptor signaling pathways.
Purpose of the Study:
- To investigate the therapeutic potential of targeting SHP2 in EGFR inhibitor-resistant NSCLC.
- To determine if inhibiting SHP2 can overcome resistance mechanisms in NSCLC.
Main Methods:
- Utilized the EGFR T790M/L858R double-mutant NSCLC cell line H1975.
- Employed siRNA to deplete SHP2 and a specific SHP2 inhibitor (II-B08).
- Assessed effects on EGF-stimulated ERK1/2 phosphorylation, cell proliferation, and tumor growth in xenograft mouse models.
- Investigated combined inhibition of SHP2 and PI3K.
Main Results:
- SHP2 is essential for EGF-stimulated ERK1/2 phosphorylation and proliferation in H1975 cells.
- Treatment with the SHP2 inhibitor II-B08 mimicked the effects of SHP2 depletion, inhibiting H1975 cell growth and ERK1/2 activation.
- II-B08 demonstrated significant anti-tumor activity in H1975 xenograft mouse models.
- Combined SHP2 and PI3K inhibition synergistically reduced H1975 cell growth by impairing both ERK1/2 and PI3K/AKT signaling.
Conclusions:
- Targeting SHP2 is a viable therapeutic strategy for EGFR inhibitor-resistant NSCLC.
- SHP2 inhibition can overcome resistance mediated by secondary EGFR mutations.
- Combined inhibition of SHP2 and PI3K may offer enhanced efficacy for treating resistant NSCLC.
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