Abstract C080: The combination of MEK and MDM2 inhibitors demonstrates promising antitumor efficacy in MAPK altered patient-derived thyroid and colorectal cancer models

Abstract

Abstract Purpose: Genomic alterations in the mitogen activated protein kinase (MAPK) pathway are common in colorectal and thyroid cancer. However MEK inhibition alone has limited efficacy. We investigated the combinatorial antitumor efficacy of MEK (Selumetinib; AZD6244) and MDM2 inhibition (AMG232) in wild-type TP53 colorectal and thyroid cancers with MAPK alterations. Methods: One thyroid (BRAF mutated) and three colorectal cancer cell lines (KRAS mutated) were used to evaluate the anti-tumor effect of selumetinib combined with AMG232 in vitro. Sulforhodamine B and colony formation assays were utilized to determine the cytotoxicity of each single targeted agent and combination and to obtain the half maximal inhibitory concentration (IC50). The efficacy of the combination was evaluated in athymic mice with subcutaneously implanted patient-derived xenografts (PDX) of different histologic backgrounds (5 colorectal and 2 thyroid cancer) and with different genomic MAPK pathway alterations. Selumetinib (25 mg/kg in 6 models, and 15 mg/kg in 1 model) and AMG232 (15 mg/kg) were administered daily through oral route. Results: Selumetinib demonstrated synergistic activity with AMG232 across all four cell lines with combination indices ranging from 0.37 to 0.72. The antitumor efficacy was enhanced when combining the two agents in all seven PDX models and achieved statistical significance in six of seven PDX models compared to either single agent therapy alone. Treatment/Control ratio % ((median tumor volume of treatment group / control group) x 100) was obtained from each combination arm across in vivo experiments (31 % (range 12%-62%)) and it was greater than monotherapy alone (Selumetinib 51%; range 21%-76%, AMG232 77%; range 38%-100%). Conclusions: Our preclinical findings demonstrate enhanced anti-tumor efficacy when combining Selumetinib with AMG232, which supports further evaluation of MEK/MDM2 inhibition in patients with MAPK altered colorectal and thyroid cancer with wild-type TP53 status. Citation Format: Seyed Pairawan, Kurt Evans, Scott Kopetz, Argun Akcakanat, Ming Zhao, Coya Tapia, Naifa Busaidy, Ecaterina Dumbrava, Funda Meric-Bernstam. The combination of MEK and MDM2 inhibitors demonstrates promising antitumor efficacy in MAPK altered patient-derived thyroid and colorectal cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C080. doi:10.1158/1535-7163.TARG-19-C080