The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma

• Published in: Cancer discovery 2016-01, Vol.6 (1), p.96-107
• Main Authors: Infarinato, Nicole R, Park, Jin H, Krytska, Kateryna, Ryles, Hannah T, Sano, Renata, Szigety, Katherine M, Li, Yimei, Zou, Helen Y, Lee, Nathan V, Smeal, Tod, Lemmon, Mark A, Mossé, Yael P
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Humans; Lactams, Macrocyclic - administration & dosage; Lactams, Macrocyclic - pharmacology; Mice; Mutation; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Neuroblastoma - metabolism; Phosphorylation - drug effects; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Pyrazoles - administration & dosage; Pyrazoles - pharmacology; Pyridines - administration & dosage; Pyridines - pharmacology; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-15-1056

Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and crizotinib-sensitive xenograft mouse models of neuroblastoma, as well as in patient-derived xenografts harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK-mutated xenograft tumors, while also inducing responses in an R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK-mutated neuroblastoma. The next-generation ALK/ROS1 inhibitor PF-06463922 exerts unparalleled activity in ALK-driven neuroblastoma models with primary crizotinib resistance. Our biochemical and in vivo data provide the preclinical rationale for fast-tracking the development of this agent in children with relapsed/refractory ALK-mutant neuroblastoma.