1. דף הבית

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

Citation:

Adi Jacob Berger, Gigi, Elinor , Kupershmidt, Lana , Meir, Zohar , Gavert, Nancy , Zwang, Yaara , Prior, Amir , Gilad, Shlomit , Harush, Uzi , Haviv, Izhak , Stemmer, Salomon M, Blum, Galia , Merquiol, Emmanuelle , Mardamshina, Mariya , Kaminski Strauss, Sivan , Friedlander, Gilgi , Bar, Jair , Kamer, Iris , Reizel, Yitzhak , Geiger, Tamar , Pilpel, Yitzhak , Levin, Yishai , Tanay, Amos , Barzel, Baruch , Reuveni, Hadas , ו Straussman, Ravid . 2021. “Irs1 Phosphorylation Underlies The Non-Stochastic Probability Of Cancer Cells To Persist During Egfr Inhibition Therapy.”. Nature Cancer, 2, 10, Pp. 1055–1070. doi:10.1038/s43018-021-00261-1.

תקציר:

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.