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Updated: Oct 21, 2025
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
High SHP2 expression determines the efficacy of PD-1/PD-L1 inhibitors in advanced KRAS mutant non-small cell lung
Hui-Bo Feng1, Yu Chen1, Zhi Xie1
1Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
Background:
Src homology region 2 domain-containing phosphatase 2 (SHP2) is a novel target for Kirsten rat sarcoma oncogene (KRAS) mutant cancer. We retrospectively studied the significance of SHP2 in KRAS mutant non-small cell lung cancer (NSCLC) treated with immunotherapy and its relationship with tumor microenvironment (TME).
Methods:
Sixty-one advanced KRAS mutant NSCLC patients who underwent immunotherapy were enrolled. Next-generation sequencing (NGS) was used to profile mutation status. The expression of SHP2, phospho-SHP2 (pSHP2), and programmed death ligand 1 (PD-L1) were analyzed by immunohistochemistry (IHC). Quantitative multiplexed immunofluorescence cytochemistry (mIFC) analysis was conducted to describe the TME.
Results:
SHP2 was heterogeneously expressed in 32 samples in both tumor cells and immune cells and highly expressed (H-score >10) in 25 (78.1%) samples. The expression levels of SHP2 and pSHP2 were positively correlated. Stromal SHP2 (s-SHP2) was higher in tumors with PD-L1 ≥50% versus PD-L1 <50% (p = 0.039). By quantitative mIFC analysis, the expression of s-SHP2 had positive correlation with CD8, CD4, CD68, and PD-L1 levels in stromal area. Patients with high SHP2 expression made up 100.0% of the partial respond (PR) and 80.0% of the stable disease (SD), whereas 50.0% of the progress disease (PD). High SHP2 expression was associated with longer progression-free survival (PFS) and overall survival (OS) (p < 0.001, p = 0.013). Patients with high expression of both SHP2 and PD-L1 had longer PFS (p < 0.001).
Conclusion:
High SHP2 expression could predict the efficacy of immunotherapy and better survival in advanced KRAS mutant NSCLC. SHP2 may function in both tumor cells and immune cells, warranting further study on the potential diverse effects of SHP2 inhibition in TME.
Insights
High SHP2 expression predicts better immunotherapy response and survival in KRAS-mutant non-small cell lung cancer (NSCLC). This finding highlights SHP2
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Src homology region 2 domain-containing phosphatase 2 (SHP2) is a potential therapeutic target in Kirsten rat sarcoma oncogene (KRAS)-mutant cancers.
- The role of SHP2 in KRAS-mutant non-small cell lung cancer (NSCLC) treated with immunotherapy and its association with the tumor microenvironment (TME) remain to be fully elucidated.
Purpose of the Study:
- To investigate the significance of SHP2 expression in KRAS-mutant NSCLC patients undergoing immunotherapy.
- To explore the relationship between SHP2 expression, tumor microenvironment (TME) characteristics, and treatment outcomes.
Main Methods:
- Retrospective analysis of 61 advanced KRAS-mutant NSCLC patients treated with immunotherapy.
- Next-generation sequencing (NGS) for mutation profiling.
- Immunohistochemistry (IHC) to assess SHP2, phospho-SHP2 (pSHP2), and programmed death ligand 1 (PD-L1) expression.
- Quantitative multiplexed immunofluorescence cytochemistry (mIFC) for detailed TME analysis.
Main Results:
- SHP2 was highly expressed in a significant proportion of NSCLC samples, correlating positively with pSHP2.
- Stromal SHP2 (s-SHP2) expression was associated with higher PD-L1 levels and increased infiltration of CD8+, CD4+, and CD68+ immune cells.
- High SHP2 expression correlated with better objective response rates (partial response and stable disease) and was linked to significantly longer progression-free survival (PFS) and overall survival (OS).
- Combined high expression of SHP2 and PD-L1 further improved PFS.
Conclusions:
- Elevated SHP2 expression serves as a predictive biomarker for immunotherapy efficacy and improved survival in advanced KRAS-mutant NSCLC.
- SHP2's multifaceted role in both tumor and immune cells suggests potential for diverse therapeutic strategies targeting SHP2 within the TME.
