Expanded clinical opportunities for crizotinib from an analysis of over 5,000 cancer patient exomes

Patients with chromosomal rearrangements resulting in fusion proteins are amongst the most responsive to targeted therapy. For example, targeting of the BCR-ABL fusion in chronic myelogenous leukemia (CML) with imatinib and the EML4-ALK fusion in non-small cell lung cancer (NSCLC) with crizotinib has led to dramatic patient responses in these diseases. While crizotinib is approved for use in EML4-ALK positive NSCLC through its inhibition of ALK, the drug also inhibits ROS1, MST1R (RON), MET, and more recently has been shown to inhibit the ALK homolog, LTK. To gain a more comprehensive understanding of the full therapeutic potential of crizotinib, we undertook a genomic survey of ALK, LTK, ROS1, MET and MST1R across thousands of patients subjected to full exome sequencing including patients from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), as well as tens thousands of patients from Oncomine® databases. We confirmed the presence of EML4-ALK fusions in both lung and colorectal cancer (CRC), identified a PRKAR1A-ALK fusion in CRC, and found evidence of novel recurrent ALK fusions in kidney papillary renal cell carcinoma and thyroid gland carcinoma. ALK hotspot mutations and focal amplifications were confined to neuroblastoma, as previously described. We also report the first instance of an LTK fusion, identified in thyroid gland carcinoma. LTK amplifications were also observed in 1.4% of gastric cancers and rarely in medulloblastoma and breast cancer. LTK was prominently over-expressed in leukemia, and in an analysis of over 4,000 PML-RARA fusion positive leukemia patients, LTK was amongst the most significantly over-expressed genes. In addition to confirming previously published ROS1 fusions, our survey of ROS1 identified rare novel fusions in NSCLC and glioblastoma. High-level MET amplifications were observed in 1-5% of papillary renal cell carcinoma, the intestinal subtype of gastric adenocarcinoma, oligodendroglioma, glioblastoma and lung adenocarcinoma. Hotspot mutations in MET were frequently observed in head and neck squamous cell carcinoma (HNSCC) (11%), and observed in a third of metastatic HNSCC samples. Additional hotspot mutations were also observed in lung adenocarcinoma (2%) and small cell lung cancer (2%). Aberrations in MST1R were rare. These results leverage all available genomic profiling data to provide a broadened scope of therapeutic opportunity for inhibitors like crizotinib. With the growing availability of next-generation sequencing data and analyses, such surveys can support hypothesis-driven development of targeted therapies and help expand opportunities for clinical stage therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C256. Citation Format: Sean Eddy, Mark Tomilo, Mary Ellen Urick, Nickolay A. Khazanov, Paul Williams, Armand Bankhead, Dinesh Cyanam, Supra Gajjala, Peter Wyngaard, Emma Bowden, Dan R. Rhodes. Expanded clinical opportunities for crizotinib from an analysis of over 5,000 cancer patient exomes. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C256.