Valencia-Sama, Ivette, Kee, Lynn, Christopher, Gabriella, Ohh, Michael, Hayes, Madeline, Irwin, Meredith S., Kee, Lynn, Mehdi, Layeghifard and Adam, Shlien (2023) SHP2 INHIBITOR TNO155 SYNERGIZES WITH ALK INHIBITORS IN ALK-DRIVEN NEUROBLASTOMA MODELS. Clinical cancer research, 3 (12). pp. 2608-2622. ISSN 2767-9764

Abstract

Purpose: Survival rates among patients with high-risk neuroblastoma remain low and novel therapies for recurrent neuroblastomas are required. ALK is commonly mutated in primary and relapsed neuroblastoma tumors and ALK tyrosine kinase inhibitors (TKIs) are promising treatments for ALK-driven neuroblastoma; however, innate or adaptive resistance to single agent ALK-TKIs remain a clinical challenge. Recently, SHP2 inhibitors have been shown to overcome ALK-TKI resistance in lung tumors harboring ALK rearrangements.
Experimental Design: We have assessed the efficacy of the SHP2 inhibitor TNO155 alone and in combination with the ALK-TKIs crizotinib, ceritinib, or lorlatinib for the treatment of ALK-driven neuroblastoma using in vitro and in vivo models.
Results: In comparison to wild-type, ALK-mutant neuroblastoma cell lines were more sensitive to SHP2 inhibition with TNO155. Treatment with TNO155 and ALK-TKIs synergistically reduced cell growth and promoted inactivation of ALK and MAPK signaling in ALK mutant neuroblastoma cell lines. ALK mutant cells engrafted into larval zebrafish and treated with single agent or dual SHP2/ALK inhibitors showed reduced growth and invasion. In murine ALK mutant xenografts, tumor growth was likewise reduced or delayed, and survival was prolonged upon combinatorial treatment of TNO155 and lorlatinib. Notably, we show that neuroblastoma cells harboring ALK-F1174L mutations that have become resistant to lorlatinib can be re-sensitized to lorlatinib when combined with TNO155 in vitro and in vivo.
Conclusions: Our results suggest that combinatorial inhibition of ALK and SHP2 could be a novel approach to treating ALK-driven neuroblastoma, including those with innate or acquired resistance to ALK inhibitors.

Item Type:	Article
Keywords:	TNO155, NSCLC, Shp2
Date Deposited:	28 Feb 2024 00:46
Last Modified:	28 Feb 2024 00:46
URI:	https://oak.novartis.com/id/eprint/49517