Lung cancer is the main cause of cancer mortality worldwide with 80% non-small cell lung cancer (NSCLC) in type and mainly driven by three mutually exclusive oncogenes, EGFR, KRAS and ALK (collectively between 30-60% of all NSCLC cases). Oncogenic drivers such as ROS1 and RET fusions and DEPDC1 over-expression have been identified as clearly recurrent, collectively constituting up to ~12% of all NSCLC cases. Preclinical studies have demonstrated ROS1-driven cancers to be exquisitely sensitive to small-molecule tyrosine kinase inhibitors (TKIs) as well as Hsp90 inhibitors that are now under development by several pharma and biotech firms. Similarly, ambiguous TKI treatments have also been used against non-NSCLC RET and DEPDC1 driven cancers in ongoing Phase I and Phase II clinical trials with good efficacy. These trials should encourage numerous pharmaceutical companies to follow suit and conduct similar clinical trials using therapeutics specifically targeting RET and DEPDC1-driven NSCLC. Unfortunately, no regulatory-approved, high-throughput commercial diagnostic tests are readily available to reliably and efficiently diagnose ROS1 or RET fusions nor DEPDC1 over expression in NSCLC patients. We propose to complete the development and validation of both a comprehensive panel of quantitative polymerase chain reaction (qPCR)-based assays and a fluorescence in situ hybridization (FISH) assay to collectively be used as a broad-based NSCLC detection panel to classify a previously unidentified, yet significant, cohort of NSCLC patients readily treatable with available therapeutics. All validations will establish clinical utility by ultimately testing a large cohort of clinical specimens to unequivocally demonstrate statistical significance for sound patient selection of inhibitor therapy. All potential companion diagnostics will then enter co-development with an IVD partner for full commercialization of each assay as a FDA-approved companion diagnostic.
