SHP2 inhibition restores sensitivity to ALK inhibitors in resistant ALK-rearranged non-small cell lung cancer

摘要

Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung tumours initially respond to small molecule ALK inhibitors but drug resistance often develops^–. After tumours develop resistance to highly potent 2^nd generation ALK inhibitors, approximately half harbor ALK resistance mutations, while the other half have other mechanisms of resistance. The latter often have activation of at least one of several different tyrosine kinases driving resistance. Such tumours are not expected to respond to the 3^rd generation ALK inhibitor, lorlatinib, which is able to overcome all clinically identified ALK resistance mutations^, and further therapeutic options are limited. Herein, we deployed an shRNA screen of 1000 genes in multiple ALK inhibitor resistant patient derived cells (PDC) to discover sensitizers to ALK inhibition. This approach identified SHP2, a non-receptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. The recently discovered small molecule SHP2 inhibitor, SHP099, in combination with the ALK TKI (tyrosine kinase inhibitor), ceritinib, halted the growth of resistant PDCs by preventing compensatory RAS and ERK1/2 reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent resistance mechanisms.