The ALK Inhibitor PF-06463922 is Effective As a Single Agent in Neuroblastoma Driven by Expression of ALK and MYCN

Overview

Journal Dis Model Mech

Specialty General Medicine

Date 2016 Aug 3

PMID 27483357

Citations 46

Authors

J Guan

E R Tucker

H Wan

D Chand

L S Danielson

K Ruuth

A El Wakil

B Witek

Y Jamin

G Umapathy

S P Robinson

T W Johnson

T Smeal

T Martinsson

L Chesler

R H Palmer

B Hallberg

Affiliations

Soon will be listed here.

Abstract

The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

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