Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer.

Autor: Gavert N; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Zwang Y; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Weiser R; Division of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Greenberg O; Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Halperin S; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Jacobi O; Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel., Mallel G; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Sandler O; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Berger AJ; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Stossel E; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Rotin D; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Grinshpun A; Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Faculty of Medicine, The Hebrew University, Jerusalem, Israel., Kamer I; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Bar J; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Pines G; Department of Thoracic Surgery, Kaplan Medical Center, Rehovot and the Faculty of Medicine, The Hebrew University, Jerusalem, Israel., Saidian D; Department of Urology, Rabin Medical Center, Petach Tikva, Israel., Bar I; Department of Thoracic Surgery, Kaplan Medical Center, Rehovot and the Faculty of Medicine, The Hebrew University, Jerusalem, Israel., Golan S; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Department of Urology, Rabin Medical Center, Petach Tikva, Israel., Rosenbaum E; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel., Nadu A; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Department of Urology, Rabin Medical Center, Petach Tikva, Israel., Ben-Ami E; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Weitzen R; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Nechushtan H; Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Faculty of Medicine, The Hebrew University, Jerusalem, Israel., Golan T; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Brenner B; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel., Nissan A; Department of General and Oncological Surgery-Surgery C, Sheba Medical Center, Ramat Gan, Israel., Margalit O; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel., Hershkovitz D; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Lahat G; Division of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Straussman R; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. ravidst@weizmann.ac.il.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2022 Feb; Vol. 3 (2), pp. 219-231. Date of Electronic Publication: 2022 Feb 10.
DOI: 10.1038/s43018-021-00325-2
Abstrakt: 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 G12 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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