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The ineffectiveness of chemotherapy in patients with pancreatic cancer highlights a critical unmet need in pancreatic cancer therapy. Two commonly mutated genes in pancreatic cancer, KRAS and CDKN2A, have an incidence exceeding 90%, supporting investigation of dual targeting of MEK and CDK4/6 as a potential therapeutic strategy for this patient population. An in vitro proliferation synergy screen was conducted to evaluate response of a panel of high passage and patient-derived pancreatic cancer models to the combination of trametinib and palbociclib to inhibit MEK and CDK4/6, respectively. Two adenosquamous carcinoma models, L3.6pl and UM59, stood out for their high synergy response. In vivo studies confirmed that this combination treatment approach was highly effective in subcutaneously implanted L3.6pl and UM59 tumor-bearing animals. Both models were refractory to single-agent treatment. Reverse-phase protein array analysis of L3.6pl tumors excised from treated animals revealed strong downregulation of COX-2 expression in response to combination treatment. Expression of COX-2 under a CMV-driven promoter and shRNA knockdown of COX-2 both led to resistance to combination treatment. Our findings suggest that COX-2 may be involved in the improved therapeutic outcome seen in some pancreatic tumors that fail to respond to MEK or CDK4/6 inhibitors alone but respond favorably to their combination.

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.