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

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

doi:10.1038/s43018-021-00325-2

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

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 NaduEytan Ben-Ami, Rony Weitzen, Hovav Nechushtan, Talia Golan, Baruch Brenner, Aviram Nissan, Ofer Margalit, Dov Hershkovitz, Guy Lahat, Ravid Straussman

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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^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.

Original language	English (US)
Pages (from-to)	219-231
Number of pages	13
Journal	Nature Cancer
Volume	3
Issue number	2
DOIs	https://doi.org/10.1038/s43018-021-00325-2
State	Published - Feb 2022
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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Gavert, N., Zwang, Y., Weiser, R., Greenberg, O., Halperin, S., Jacobi, O., Mallel, G., Sandler, O., Berger, A. J., Stossel, E., Rotin, D., Grinshpun, A., Kamer, I., Bar, J., Pines, G., Saidian, D., Bar, I., Golan, S., Rosenbaum, E., ... Straussman, R. (2022). Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer. Nature Cancer, 3(2), 219-231. https://doi.org/10.1038/s43018-021-00325-2

Gavert, N, Zwang, Y, Weiser, R, Greenberg, O, Halperin, S, Jacobi, O, Mallel, G, Sandler, O, Berger, AJ, Stossel, E, Rotin, D, Grinshpun, A, Kamer, I, Bar, J, Pines, G, Saidian, D, Bar, I, Golan, S, Rosenbaum, E, Nadu, A, Ben-Ami, E, Weitzen, R, Nechushtan, H, Golan, T, Brenner, B, Nissan, A, Margalit, O, Hershkovitz, D, Lahat, G & Straussman, R 2022, 'Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer', Nature Cancer, vol. 3, no. 2, pp. 219-231. https://doi.org/10.1038/s43018-021-00325-2

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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 KRASG12 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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AU - Jacobi, Oded

AU - Mallel, Giuseppe

AU - Sandler, Oded

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AU - Stossel, Erez

AU - Rotin, Daniil

AU - Grinshpun, Albert

AU - Kamer, Iris

AU - Bar, Jair

AU - Pines, Guy

AU - Saidian, Daniel

AU - Bar, Ilan

AU - Golan, Shay

AU - Rosenbaum, Eli

AU - Nadu, Andrei

AU - Ben-Ami, Eytan

AU - Weitzen, Rony

AU - Nechushtan, Hovav

AU - Golan, Talia

AU - Brenner, Baruch

AU - Nissan, Aviram

AU - Margalit, Ofer

AU - Hershkovitz, Dov

AU - Lahat, Guy

AU - Straussman, Ravid

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N2 - 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 KRASG12 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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Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer

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