Sensitivity of colorectal or pancreatic cancers with high DDX5 and mutations in Kras and p53 genes to FL118 treatment.

e16102 Background: FL118 is a small molecule anticancer drug with novel mechanisms of action, although its chemical structure is similar to camptothecins. Currently, FL118 is completing its IND process to enter clinical trials for patients with advanced colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) cancers. Precision medicine is becoming a trend for modern cancer treatment. Thus, identification of drug efficacy-relevant biomarker(s) for patient selection is critical for enhancing patients’ response rates and avoiding unnecessary treatment in the clinic. Methods: Animal models of CRC and PDAC patient-derived xenograft (PDX) tumors were used to test FL118 efficacy; next generation sequencing (NGS) was used to determine PDX tumor molecular profiles; Western blots (WB) and real time RT-PCR were used to determine gene expression and/or apoptosis; Immunoprecipitation (IP) plus WB was used to determine protein phophorylation. Proteasome inhibitor was used to determine protein expression pathway. FL118 affinity purification was used to identify FL118 binding protein(s). Results: In association with WuXi Apptec, we have completed FL118 CMC and produced a clinical compatible product formulation. In this new product format, FL118 exhibits excess toxicity at a dose of ≥ 7.5 mg/kg via weekly x 4 schedules in mice. However, dosages of ≤ 6 mg/kg via the same schedule are tolerable. FL118 can eliminate the Kras/p53/APC triple-mutated SW620-established CRC tumors in a high percentage of mice at doses of 6 (maximum tolerated dose, MTD), 5, 4, 3, and 2 mg/kg. Tumor elimination under MTD is a typical characteristic of targeted drugs, which do not need MTD but only need the target to be saturated with drug for maximal efficacy. High expression of DDX5 (also called p68), a multifunctional oncogenic transcriptional co-activator and a DEAD-box RNA helicase, is associated with high FL118 efficacy in both CRC and PDAC PDX tumors. Mechanistically, FL118 binds to DDX5 to induce DDX5 tyrosine dephosphorylation and protein degradation without decreasing its mRNA. Tumors with Kras mutation (mKras) and/or TP53/p53 mutation (mp53) possess intrinsic resistance to multiple classic chemotherapeutic agents. However, PDAC PDX tumors with mp53 exhibit higher mKras expression and greater sensitivity to FL118 than tumors with wild type p53 and mKras. Conclusions: DDX5, mKras and mp53 appears to be favorable biomarkers for predicting FL118 high efficacy. However, further studies with a large cohort will be needed for confirmation.