Using SHP1 Expression to Predict Response to Ibrutinib in Diffuse Large B-Cell Lymphoma

By: Joseph Fanelli
Posted: Friday, February 11, 2022

The expression of the cytosolic protein tyrosine phosphatase SHP1 is suppressed in a “substantial” number of patients with diffuse large B-cell lymphoma (DLBCL) tumors, making it a potential biomarker to predict the effectiveness of treatment with the tyrosine kinase inhibitor ibrutinib, according to findings presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 3490). The loss of SHP1 increases B-cell receptor activity and sensitizes tumor cells to the inhibition by ibrutinib, concluded Wenjun Wu, PhD, of Fox Chase Cancer Center, Philadelphia, and colleagues.

“From a therapeutic perspective, our results suggest that reducing SHP1 pharmacologically may represent a strategy to augment tumor response to B-cell receptor–directed therapies,” stated initial study author, Y. Lynn Wang, MD, PhD, also of Fox Chase, in an institutional press release.

In this trial, the authors first reviewed published literature on SHP1 in patients with non-Hodgkin’s lymphoma. The analysis of the SHP1 protein expression by immunohistochemistry revealed that a lack of SHP1 expression was found in 178 of 242 non-Hodgkin’s lymphoma tissues (73.6%), compared with 32 of 264 normal or benign control tissues (12%). The odds ratio derived by the meta-analysis was 119.58, suggesting the loss of SHP1 may be strongly associated with non-Hodgkin’s lymphoma, including DLBCL.

Additionally, the authors constructed a tissue microarray with 48 DLBCL tumors and 12 cell lines. From the cell lines, they identified a strong reverse linear correlation between SHP1 protein expression and promoter methylation, which suggests the latter may be responsible for reduced SHP1 expression in DLBCL cells.

Using CRISPR, the authors determined that the phosphorylation of early B-cell receptor components—BTK, SYK, and LYN—was increased in the SHP1 knockout clones compared with the wild-type versions. This showed that SHP1 depletion tends to result in increased proximal B-cell receptor–signaling activity. Additionally, the knockout clones displayed an increased sensitivity to ibrutinib.

Disclosure: For disclosures of the study authors, visit ash.com.

2021 ASH Annual Meeting & Exposition

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