Overcoming Resistance: The Potency of PF-06463922 Against Oncogenic ROS1 Fusions and the ROS1G2032R Mutant in Preclinical Tumor Models

The ROS1 gene fusion has been identified as a significant factor in various human cancers, making it a promising target for cancer therapy. While the first-generation Met/ALK/ROS1 inhibitor crizotinib has shown clinical benefits for ROS1 fusion-positive non-small cell lung cancer (NSCLC), resistance mutations, such as ROS1G2032R, have emerged, necessitating the development of new agents to overcome this resistance.

PF-06463922 is a novel, potent, and orally available small molecule inhibitor of ROS1/ALK, with high efficacy against ROS1 kinase. It has shown sub-nanomolar inhibition of ROS1 autophosphorylation across a range of cell lines with different ROS1 fusion variants. PF-06463922 also effectively inhibits cell proliferation and induces apoptosis in HCC78 human NSCLC cells and BaF3 cells expressing ROS1 fusions. Notably, it has demonstrated nanomolar potency against the crizotinib-resistant ROS1G2032R mutant both in cellular activity and cell proliferation.

In vivo studies have confirmed PF-06463922's significant antitumor efficacy at low nanomolar concentrations in xenograft models with human ROS1 fusions. Its antitumor effects are dose-dependent and correlated with the inhibition of ROS1 phosphorylation, downstream signaling molecules, and cell cycle protein Cyclin D1.

PF-06463922 is the first reported ROS1 inhibitor capable of blocking the resistant ROS1G2032R mutant at pharmacologically relevant concentrations. The data support the potential of PF-06463922 in treating ROS1 fusion-positive cancers, including those that have developed resistance to crizotinib therapy due to the acquired ROS1G2032R mutation.