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

School of Pharmacy

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

Bibliographical note

Funding Information:
We thank D. Douek, I. Ben-Porath and O. Sandler for their comments. We thank Champions Oncology for providing HNSCC patient tumor microarrays and PDX data. We thank M. Berger for assistance with the preparation of the figures. R.S. was partially funded by the Fabrikant-Morse Families Research Fund for Humanity, the Moross Integrated Cancer Center and the Rising Tide Foundation. R.S. is the incumbent of the Roel C. Buck Career Development Chair. I.H. was partially funded by Leona M. and Harry B. Helmsley Charitable Trust grant no. 2012PG-ISL013. I.H. and S.M.S. were partially funded by the Rabin Medical Center–Bar-Ilan grant project. G.F. is the incumbent of the David and Stacey Cynamon Research fellow Chair in Genetics and Personalized Medicine.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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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.",

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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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AU - Jacob Berger, Adi

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AU - Kupershmidt, Lana

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AU - Gavert, Nancy

AU - Zwang, Yaara

AU - Prior, Amir

AU - Gilad, Shlomit

AU - Harush, Uzi

AU - Haviv, Izhak

AU - Stemmer, Salomon M.

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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

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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.

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

Abstract

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