Targeting ROS1 with Anaplastic Lymphoma Kinase Inhibitors: A Promising Therapeutic Strategy for a Newly Defined Molecular Subset of Non–Small-Cell Lung.

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Targeting ROS1 with Anaplastic Lymphoma Kinase Inhibitors: A Promising Therapeutic Strategy for a Newly Defined Molecular Subset of Non–Small-Cell Lung Cancer Leow Pay Chin, PhD, Ross A. Soo, MD, Richie Soong, PhD, Sai-Hong I. Ou, MD, PhD Journal of Thoracic Oncology Volume 7, Issue 11, Pages 1625-1630 (November 2012) DOI: 10.1097/JTO.0b013e31826baf83 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 ROS1 signaling pathways. ROS1 engages multiple signalling pathways to exert its transformation activity. PLCγ, MAP kinase, IRS1 (signalling molecule to PI3K), VAV3, STATS, cytoskeleton and cell-to-cell interaction (β-integrin, tensin, α-, β-, Δ-catenin, N-catenin) proteins can interact with ROS1, and phospohorylation of these proteins by ROS1 can lead to activation of the respective oncogenic pathways. ROS autophosphorylation sites are docking sites for the tyrosine phosphatases SHP-1 and SHP, Src-homology 2 domain-containing phosphatase; ROS1, c-ros oncogene 1, receptor tyrosine kinase c-ros oncogene 1, receptor tyrosine kinase; PLCγ, phospholipase C, gamma; MAP, mitogen-activated protein kinase; IRS1, insulin receptor substrate 1; VAV3, vav 3 guanine nucleotide exchange factor 1; STATS, signal transducers and activators of transcription-3; PDK1, pyruvate dehydrogenase kinase, isozyme 1; AKT (v-akt murine thymoma viral oncogene homolog 1); mTOR, mechanistic target of rapamycin (serine/threonine kinase); P13K, phosphoinositide-3 kinase; and RHO, rhodopsin. Journal of Thoracic Oncology 2012 7, 1625-1630DOI: (10.1097/JTO.0b013e31826baf83) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 ROS1 fusion variants described in non–small-cell lung cancer. The breakpoints of ROS1 are located at exons 32 (e32), 34 (e34), and 35 (e35). All the ROS1 variants harbor the kinase domain whereas the exon 32 breakpoint allows the resulting fusion variants to harbor the TM. In the fusion partners, orange and dark green represent coiled-coil and transmembrane domains, respectively. TM, transmembrane domain; and PD2,. Journal of Thoracic Oncology 2012 7, 1625-1630DOI: (10.1097/JTO.0b013e31826baf83) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions