Inhibition of ErbB3 and Associated Regulatory Pathways Potently Impairs Malignant Peripheral Nerve Sheath Tumor Proliferation and Survival

by Selleckchem | Oct 16 2023

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive MAPK and mTOR signaling pathways. To identify potential therapeutic targets, we previously performed genome-scale shRNA screens that implicated the neuregulin-1 (NRG1) receptor erbB3 in MPNST proliferation and/or survival. Here, we show that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src and erbB3 mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, calmodulin) and parallel (AZD1208) signaling pathways involving MAPK and mTOR reduced MPNST proliferation and survival. ErbB inhibitors (canertinib, sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin (trifluoperazine) or PIM kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied CaMKII phosphorylation site in a Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and trifluoperazine-induced erbB3 and CaMKII phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events and when combined with trifluoperazine even more effectively reduces proliferation and survival compared to monotherapy. Our findings implicate erbB3, calmodulin, PIM kinases and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.

Comments:

Your statement describes a study that investigated potential therapeutic targets for malignant peripheral nerve sheath tumors (MPNSTs), which are aggressive and currently difficult to treat. The researchers performed genome-scale shRNA screens and found that the neuregulin-1 (NRG1) receptor erbB3 is involved in MPNST proliferation and survival. They confirmed that erbB3 is commonly expressed in MPNSTs and cell lines and demonstrated that knocking down erbB3 inhibits MPNST proliferation and survival.

The study also conducted kinomic and microarray analyses of Schwann and MPNST cells, which revealed that signaling pathways involving Src and erbB3-mediated calmodulin-regulated signaling are crucial in MPNSTs. Inhibition of upstream pathways (canertinib, sapitinib, saracatinib, calmodulin) and parallel pathways (AZD1208) related to MAPK and mTOR resulted in reduced MPNST proliferation and survival. Additionally, combining erbB inhibitors (canertinib, sapitinib) or erbB3 knockdown with inhibitors of Src (saracatinib), calmodulin (trifluoperazine), or PIM kinase (AZD1208) further enhanced the reduction in proliferation and survival.

The researchers also discovered an unknown phosphorylation site on CaMKII, which was increased by drug inhibition in a Src-dependent manner. Treatment with the Src family kinase inhibitor saracatinib reduced both basal and trifluoperazine-induced erbB3 and CaMKII phosphorylation. Src inhibition and erbB3 knockdown prevented these phosphorylation events, and when combined with trifluoperazine, they were even more effective in reducing proliferation and survival compared to monotherapy.

Overall, this study suggests that erbB3, calmodulin, PIM kinases, and Src family members are potential therapeutic targets in MPNSTs. The findings highlight the importance of combination therapies that target critical signaling pathways in MPNSTs to achieve better treatment outcomes.