IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy

Adi Jacob Berger; Elinor Gigi; Lana Kupershmidt; Zohar Meir; Nancy Gavert; Yaara Zwang; Amir Prior; Shlomit Gilad; Uzi Harush; Izhak Haviv; Salomon M. Stemmer; Galia Blum; Emmanuelle Merquiol; Mariya Mardamshina; Sivan Kaminski Strauss; Gilgi Friedlander; Jair Bar; Iris Kamer; Yitzhak Reizel; Tamar Geiger; Yitzhak Pilpel; Yishai Levin; Amos Tanay; Baruch Barzel; Hadas Reuveni; Ravid Straussman

doi:10.1038/s43018-021-00261-1

IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy

Adi Jacob Berger, Elinor Gigi, Lana Kupershmidt, Zohar Meir, Nancy Gavert, Yaara Zwang, Amir Prior, Shlomit Gilad, Uzi Harush, Izhak Haviv, Salomon M. Stemmer, Galia Blum, Emmanuelle Merquiol, Mariya Mardamshina, Sivan Kaminski Strauss, Gilgi Friedlander, Jair Bar, Iris Kamer, Yitzhak Reizel, Tamar GeigerYitzhak Pilpel, Yishai Levin, Amos Tanay, Baruch Barzel, Hadas Reuveni, Ravid Straussman^*

^*Corresponding author for this work

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

15 Scopus citations

Abstract

Stochastic transition of cancer cells between drug-sensitive and drug-tolerant persister phenotypes has been proposed to play a key role in non-genetic resistance to therapy. Yet, we show here that cancer cells actually possess a highly stable inherited chance to persist (CTP) during therapy. This CTP is non-stochastic, determined pre-treatment and has a unimodal distribution ranging from 0 to almost 100%. Notably, CTP is drug specific. We found that differential serine/threonine phosphorylation of the insulin receptor substrate 1 (IRS1) protein determines the CTP of lung and of head and neck cancer cells under epidermal growth factor receptor inhibition, both in vitro and in vivo. Indeed, the first-in-class IRS1 inhibitor NT219 was highly synergistic with anti-epidermal growth factor receptor therapy across multiple in vitro and in vivo models. Elucidation of drug-specific mechanisms that determine the degree and stability of cellular CTP may establish a framework for the elimination of cancer persisters, using new rationally designed drug combinations.

Original language	English
Pages (from-to)	1055-1070
Number of pages	16
Journal	Nature Cancer
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s43018-021-00261-1
State	Published - Oct 2021

Funding

Funders	Funder number
Fabrikant-Morse Families Research Fund for Humanity
Moross Integrated Cancer Center
Rabin Medical Center
Leona M. and Harry B. Helmsley Charitable Trust	2012PG-ISL013
Rising Tide Foundation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s43018-021-00261-1

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Jacob Berger, A., Gigi, E., Kupershmidt, L., Meir, Z., Gavert, N., Zwang, Y., Prior, A., Gilad, S., Harush, U., Haviv, I., Stemmer, S. M., Blum, G., Merquiol, E., Mardamshina, M., Kaminski Strauss, S., Friedlander, G., Bar, J., Kamer, I., Reizel, Y., ... Straussman, R. (2021). IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy. Nature Cancer, 2(10), 1055-1070. https://doi.org/10.1038/s43018-021-00261-1

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title = "IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy",

abstract = "Stochastic transition of cancer cells between drug-sensitive and drug-tolerant persister phenotypes has been proposed to play a key role in non-genetic resistance to therapy. Yet, we show here that cancer cells actually possess a highly stable inherited chance to persist (CTP) during therapy. This CTP is non-stochastic, determined pre-treatment and has a unimodal distribution ranging from 0 to almost 100%. Notably, CTP is drug specific. We found that differential serine/threonine phosphorylation of the insulin receptor substrate 1 (IRS1) protein determines the CTP of lung and of head and neck cancer cells under epidermal growth factor receptor inhibition, both in vitro and in vivo. Indeed, the first-in-class IRS1 inhibitor NT219 was highly synergistic with anti-epidermal growth factor receptor therapy across multiple in vitro and in vivo models. Elucidation of drug-specific mechanisms that determine the degree and stability of cellular CTP may establish a framework for the elimination of cancer persisters, using new rationally designed drug combinations.",

author = "{Jacob Berger}, Adi and Elinor Gigi and Lana Kupershmidt and Zohar Meir and Nancy Gavert and Yaara Zwang and Amir Prior and Shlomit Gilad and Uzi Harush and Izhak Haviv and Stemmer, {Salomon M.} and Galia Blum and Emmanuelle Merquiol and Mariya Mardamshina and {Kaminski Strauss}, Sivan and Gilgi Friedlander and Jair Bar and Iris Kamer and Yitzhak Reizel and Tamar Geiger and Yitzhak Pilpel and Yishai Levin and Amos Tanay and Baruch Barzel and Hadas Reuveni and Ravid Straussman",

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month = oct,

doi = "10.1038/s43018-021-00261-1",

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Jacob Berger, A, Gigi, E, Kupershmidt, L, Meir, Z, Gavert, N, Zwang, Y, Prior, A, Gilad, S, Harush, U, Haviv, I, Stemmer, SM, Blum, G, Merquiol, E, Mardamshina, M, Kaminski Strauss, S, Friedlander, G, Bar, J, Kamer, I, Reizel, Y, Geiger, T, Pilpel, Y, Levin, Y, Tanay, A, Barzel, B, Reuveni, H & Straussman, R 2021, 'IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy', Nature Cancer, vol. 2, no. 10, pp. 1055-1070. https://doi.org/10.1038/s43018-021-00261-1

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T1 - IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy

AU - Jacob Berger, Adi

AU - Gigi, Elinor

AU - Kupershmidt, Lana

AU - Meir, Zohar

AU - Gavert, Nancy

AU - Zwang, Yaara

AU - Prior, Amir

AU - Gilad, Shlomit

AU - Harush, Uzi

AU - Haviv, Izhak

AU - Stemmer, Salomon M.

AU - Blum, Galia

AU - Merquiol, Emmanuelle

AU - Mardamshina, Mariya

AU - Kaminski Strauss, Sivan

AU - Friedlander, Gilgi

AU - Bar, Jair

AU - Kamer, Iris

AU - Reizel, Yitzhak

AU - Geiger, Tamar

AU - Pilpel, Yitzhak

AU - Levin, Yishai

AU - Tanay, Amos

AU - Barzel, Baruch

AU - Reuveni, Hadas

AU - Straussman, Ravid

PY - 2021/10

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N2 - Stochastic transition of cancer cells between drug-sensitive and drug-tolerant persister phenotypes has been proposed to play a key role in non-genetic resistance to therapy. Yet, we show here that cancer cells actually possess a highly stable inherited chance to persist (CTP) during therapy. This CTP is non-stochastic, determined pre-treatment and has a unimodal distribution ranging from 0 to almost 100%. Notably, CTP is drug specific. We found that differential serine/threonine phosphorylation of the insulin receptor substrate 1 (IRS1) protein determines the CTP of lung and of head and neck cancer cells under epidermal growth factor receptor inhibition, both in vitro and in vivo. Indeed, the first-in-class IRS1 inhibitor NT219 was highly synergistic with anti-epidermal growth factor receptor therapy across multiple in vitro and in vivo models. Elucidation of drug-specific mechanisms that determine the degree and stability of cellular CTP may establish a framework for the elimination of cancer persisters, using new rationally designed drug combinations.

AB - Stochastic transition of cancer cells between drug-sensitive and drug-tolerant persister phenotypes has been proposed to play a key role in non-genetic resistance to therapy. Yet, we show here that cancer cells actually possess a highly stable inherited chance to persist (CTP) during therapy. This CTP is non-stochastic, determined pre-treatment and has a unimodal distribution ranging from 0 to almost 100%. Notably, CTP is drug specific. We found that differential serine/threonine phosphorylation of the insulin receptor substrate 1 (IRS1) protein determines the CTP of lung and of head and neck cancer cells under epidermal growth factor receptor inhibition, both in vitro and in vivo. Indeed, the first-in-class IRS1 inhibitor NT219 was highly synergistic with anti-epidermal growth factor receptor therapy across multiple in vitro and in vivo models. Elucidation of drug-specific mechanisms that determine the degree and stability of cellular CTP may establish a framework for the elimination of cancer persisters, using new rationally designed drug combinations.

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JO - Nature Cancer

JF - Nature Cancer

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ER -

IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy

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UN SDGs

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