The Oncogenic Lung Cancer Fusion Kinase CD74-ROS Activates a Novel Invasiveness Pathway through E-Syt1 Phosphorylation

Jun, Hyun Jung; Johnson, Hannah; Bronson, Roderick T.; Feraudy, Sébastien de; White, Forest M.; Charest, Alain

doi:10.1158/0008-5472.can-11-3990

Cited by 106 publications

(60 citation statements)

References 32 publications

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“…We also identified multiple c-ros oncogene 1 ( ROS1 ) fusions, including ROS1 fusions in 8/513 lung adenocarcinomas, all of which have been previously described9101112. In addition, we detected a CEP85L – ROS1 fusion in a glioblastoma tumour sample (Fig.…”

Section: Resultsmentioning

confidence: 75%

The landscape of kinase fusions in cancer

et al. 2014

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Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been characterized as extensively. Here we develop heuristics for reliably detecting gene fusion events in RNA-seq data and apply them to nearly 7,000 samples from The Cancer Genome Atlas. We thereby are able to discover several novel and recurrent fusions involving kinases. These findings have immediate clinical implications and expand the therapeutic options for cancer patients, as approved or exploratory drugs exist for many of these kinases.

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Section: Resultsmentioning

confidence: 75%

The landscape of kinase fusions in cancer

et al. 2014

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“…Previously we demonstrated that ROS1 fusion kinases preferentially signal through the tyrosine phosphatase Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) and activate both the MEK1/2-ERK1/2 and the AKT/mTORC1 signaling axes (32,33). Therefore, we evaluated the impact of PF-06463922 on these pathways.…”

Section: Pf-06463922 Potency In Cells Expressingmentioning

confidence: 99%

PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

Zou¹,

Li²,

Engstrom³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

231

167

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Oncogenic c-ros oncogene1 (ROS1) fusion kinases have been identified in a variety of human cancers and are attractive targets for cancer therapy. The MET/ALK/ROS1 inhibitor crizotinib (Xalkori, PF-02341066) has demonstrated promising clinical activity in ROS1 fusion-positive non-small cell lung cancer. However, emerging clinical evidence has shown that patients can develop resistance by acquiring secondary point mutations in ROS1 kinase. In this study we characterized the ROS1 activity of PF-06463922, a novel, orally available, CNS-penetrant, ATP-competitive small-molecule inhibitor of ALK/ROS1. In vitro, PF-06463922 exhibited subnanomolar cellular potency against oncogenic ROS1 fusions and inhibited the crizotinib-refractory ROS1 G2032R mutation and the ROS1 G2026M gatekeeper mutation. Compared with crizotinib and the second-generation ALK/ROS1 inhibitors ceritinib and alectinib, PF-06463922 showed significantly improved inhibitory activity against ROS1 kinase. A crystal structure of the PF-06463922-ROS1 kinase complex revealed favorable interactions contributing to the high-affinity binding. Taken together, our results indicate that PF-06463922 has potential for treating ROS1 fusion-positive cancers, including those requiring agents with CNS-penetrating properties, as well as for overcoming crizotinib resistance driven by ROS1 mutation.PF-06463922 | ROS1 | kinase inhibitor R eceptor tyrosine kinases (RTKs) are vital conduits of extracellular signals that direct cell growth and survival pathways. Unregulated RTK activation through chromosomal rearrangements, point mutations, and gene amplification has been shown to be responsible for the initiation and progression of many cancers. The orphan RTK c-ros oncogene1 (ROS1) normally is expressed transiently in various tissues during development with little to no expression in adult tissues (1). Elevated full-length c-ROS1 expression levels have been observed in 20-30% of patients with nonsmall cell lung cancer (NSCLC) by gene expression profiling (2-4) and in 13% of patients with lung adenocarcinoma using immunohistochemistry (IHC) (5). However, its function, both in normal physiology and disease, remains poorly defined mainly because of its still unidentified ligand. Chromosomal rearrangements resulting in oncogenic activation of ROS1 have been observed in a subset of patients with glioblastoma (6-9), NSCLC (10-14), cholangiocarcinoma (15), ovarian cancer (16), angiosarcoma (17), inflammatory myofibroblastic tumors (18), and Spitzoid melanoma (19). To date, interchromosomal translocations or intrachromosomal deletions have resulted in the production of 20 different N-terminal ROS1 fusion genes in a variety of cancers (Table S1).ROS1 is a distinct receptor with a kinase domain that is phylogenetically related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (ALK/LTK) and insulin receptor (INSR) RTK families (20), suggesting that tyrosine kinase inhibitors for these receptors could have cross-activity against ROS1. A recent phase I/II cl...

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“…The downstream signalling cascade is achieved by navigating through phosphoinositide 3 kinase/mammalian target of rapamycin pathway, phosphorylation/activation of signal transducers and activators of transcription 3 (STAT3) and vav 3 guanine nucleotide exchange factor 1 eventually leading to regulation of anchorage-independent cellular growth and cell morphology 8 12–16. Interestingly, in a recent report, Jun et al demonstrated that the activation of downstream signalling pathways differ based on fusion partners of ROS1, as phosphorylation/activation of E-Syt1 (extended synaptotagmin 1) led to an invasive phenotype in CD74-ROS1 transduced cells, but not in FIG-ROS1 transduced cells 15 Figure 2. summarises14 the key downstream signalling pathways known to be involved in downstream cell proliferation, survival, migration and metastasis, transformation and invasiveness 8 14…”

Section: Ros1 Signalling Pathwaymentioning

confidence: 98%

ROS1-1

Pal

Khan

2017

J Clin Pathol

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ROS1 is a receptor tyrosine kinase that has recently been shown to undergo gene rearrangements in~1%-2% of non-small cell lung carcinoma (NSCLC) and in a variety of other tumours including cholangiocarcinoma, gastric carcinoma, colorectal carcinoma and in spitzoid neoplasms, glioblastoma and inflammatory myofibroblastic tumours. The ROS1 gene fusion undergoes constitutive activation, regulates cellular proliferation and is implicated in carcinogenesis. ROS1 fusions can be detected by fluorescence in situ hybridisation, real-time PCR, sequencing-based techniques and immunohistochemistry-based methods in clinical laboratories. The small molecule tyrosine kinase inhibitor, crizotinib has been shown to be an effective inhibitor of ROS1 and has received Food and Drug Administration approval for treatment of advanced NSCLC. The current review is an update on the clinical findings and detection methods of ROS1 in clinical laboratories in NSCLC and other tumours.

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The Oncogenic Lung Cancer Fusion Kinase CD74-ROS Activates a Novel Invasiveness Pathway through E-Syt1 Phosphorylation

Cited by 106 publications

References 32 publications

The landscape of kinase fusions in cancer

The landscape of kinase fusions in cancer

PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

ROS1-1

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