Abstract 2644: Comparison of PDMR cell line complex spheroid response and PDX response to trametinib
Authors: Teicher Beverly A. , Coussens Nathan P. , Hollingshead Melinda , Wright John , Silvers Thomas , Delosh Rene , Laudeman Julie , Reinhart Russell , Ogle Chad , Doroshow James 
Published: July 2021

Abstract
The NCI is engaged in developing a large resource of well-characterized patient-derived xenografts and corresponding cell lines and organoid cultures which are available to the global cancer research community (https://pdmr.cancer.gov/models/database.htm). The current study explored trametinib in PDMR models including cell lines and PDX tumors. Trametinib is a selective reversible allosteric inhibitor of MEK1 and MEK2 activity. The RAS-RAF-MEK-ERK pathway is important in cell proliferation and differentiation and is active in many cancers. Twenty-one PDMR lines were grown as complex spheroids, tumor cells mixed with HUVEC and MSC, to model human solid tumors. Complex spheroids were established for 3 days before drug was added. Seven days after drug addition the experiment was terminated with CellTiter-Glo 3D. Cell viability was determined relative to vehicle treated control and IC50 values calculated from concentration response data. Response to trametinib was assessed over a concentration range (0.0001 - 0.03 μM) achievable in patients. The clinical Cmax concentration for trametinib is 0.021 μM. 3 cell lines did not reach an IC50 at 0.02 μM. PDX studies were performed in 5 PDMR models. Three lines were derived from one pancreatic cancer patient: 521955-158-R2-J5 was from a liver metastasis; 521955-158-R6-J3 was from a myometrium metastasis; and 521955-158-R7-J2 was from a colon metastasis. The trametinib IC50 values for the 521955-158-R2, 521955-158-R7 and 128128-338-R lines ranged from 0.001 - 0.0015 μM. The 521955-158-R6 line was resistant with an IC50 of 0.03 μM. The 349418-098-R NSCLC line, which harbors a BRAF V600E mutation, was sensitive to trametinib with an IC50 value of 0.0002 μM. PDX studies had 8-15 mice in control groups and 6-15 mice in treated groups. The PDX models, 128128-338-R, 521955-158-R6, 521955-158-R7, 877537-175-T-J1 and 349418-098-R, responded rapidly to trametinib but had modest to moderate responses with all 5 tumors reaching maximal responses ranging between 25 and 50% of control tumor volume. The PDX tumors had a range of growth rates taking between 14 and 45 days to reach volumes of 150-200 mm3, to begin treatment. Trametinib was administered, in 10% DMSO/5% Cremophor orally once daily for 28 days. During the treatment period tumor quadrupling times were 128128-338-R, controls 21days and treated 36 days; 521955-158-R6, controls 15 days and treated 40 days; 521955-158-R7, controls 17 days and treated 35 days; 977537-175-T-J1, controls 6 days and treated 18 days and 349418-098-R, controls 19 days and treated 32 days. The differences in tumor response were not sufficient to find a correlation with spheroid response, although the 128128-338-R model which had the lowest IC50 value also had the greatest tumor response as determined by T/C volume ratio. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E.
Citation Format: Beverly A. Teicher, Nathan P. Coussens, Melinda Hollingshead, John Wright, Thomas Silvers, Rene Delosh, Julie Laudeman, Russell Reinhart, Chad Ogle, James Doroshow. Comparison of PDMR cell line complex spheroid response and PDX response to trametinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2644.