Abstract 2196: Strong anti-tumor activity of MEK inhibitor GDC-0623 and determination of predictive biomarkers
Authors: Vuaroqueaux Vincent , Hasani Hoor Al , Kelter Gerhard , Hendriks Hans R , Fiebig Heinz-Herbert 
Published: August 2019

MEK inhibitors emerged as a promising class of anti-cancer agents to inhibit KRAS/RAF driven tumors like melanoma and colorectal cancer. GDC-0623 is a potent ATP-noncompetitive allosteric MEK1 inhibitor. The compound forms a strong hydrogen bond with Ser212 of MEK1, blocking MEK feedback phosphorylation of wild-type RAF. Preclinical studies showed efficacy in vitro and in vivo and in a phase I clinical study, suggesting that the compound has clinical potential. In the present work, we aimed to define candidate tumors to GDC-0623 treatment and gain insight into biomarkers and predictive models of response.

GDC-0623 was tested in vitro in a 2D monolayer assay (260 human tumor cell lines of 36 histological subtypes). Next, activity was tested in vivo in a human tumor cell line engrafted subcutaneously in nude mice. Drug sensitivity results were then bound to molecular information of the tumor models, including whole exome mutations, gene copy number variations and gene expression profiles, to identify determinants and build a predictor of response.

In vitro, GDC-0623 showed a strong anti-tumor activity (abs. IC70 &lt;1 µM) in a wide range of blood and solid tumors. IC50 values varied from 0.001 to &gt;30 µM (Geometric mean: 2.95 µM). The majority of leukemia CML and AML cell lines were sensitive (4/7 and 6/11, respectively) whereas lymphoma cell lines were mainly resistant. In solid tumors, strong activity was seen in almost all melanoma cell lines (10/12) and similar activity was observed in 5/8 bladder, 10/16 colon, 7/12 head and neck, 5/12 pancreas, 4/12 gastric and 4/12 breast cell lines. Anti-tumor activity of GDC-0623 was confirmed in vivo in the human colon HTX model COLO-205 (BRAF V600E mutant). An oral dose of 40 mg/kg/day caused a strong inhibition of the tumor growth (T/C = 6%) without impacting animal body weight.

Screening of cell lines for molecular features associated with response showed BRAF V600E, NRAS Q61K, Q61R and DUSP27 gene mutations among the strongest predictors of response (Fisher test, p &lt;0.05). Furthermore, cell lines with EGFR and MET amplifications were almost all sensitive (4/5 and 3/4, respectively, Fisher p&lt;0.03). At transcriptome levels, a total 2108 genes were significantly associated with response to GDC-0623 (intersection of Spearman and Limma tests, adjusted p values &lt;0.05). Integrative analysis with significant genomic and transcriptomic parameters is currently ongoing to develop a molecular predictor of response to GDC-0623. Extending evaluation of the compound in vivo and validating predictors of response are needed to complete these preclinical investigations.

Citation Format: Vincent Vuaroqueaux, Hoor Al Hasani, Gerhard Kelter, Hans R Hendriks, Heinz-Herbert Fiebig. Strong anti-tumor activity of MEK inhibitor GDC-0623 and determination of predictive biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2196.