Ex Vivo Organotypic Cultures for Synergistic Therapy Prioritization Identify Patient-specific Responses to Combined MEK and Src Inhibition in Colorectal Cancer

Overview

Journal Nat Cancer

Specialty Oncology

Date 2022 Feb 11

PMID 35145327

Authors

Nancy Gavert

Yaara Zwang

Roi Weiser

Orli Greenberg

Sharon Halperin

Oded Jacobi

Giuseppe Mallel

Oded Sandler

Adi Jacob Berger

Erez Stossel

Daniil Rotin

Albert Grinshpun

Iris Kamer

Jair Bar

Guy Pines

Daniel Saidian

Ilan Bar

Shay Golan

Eli Rosenbaum

Andrei Nadu

Eytan Ben-Ami

Rony Weitzen

Hovav Nechushtan

Talia Golan

Baruch Brenner

Aviram Nissan

Ofer Margalit

Dov Hershkovitz

Guy Lahat

Ravid Straussman

Affiliations

Soon will be listed here.

Abstract

Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRAS mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.

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