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IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy.
- Source :
-
Nature cancer [Nat Cancer] 2021 Oct; Vol. 2 (10), pp. 1055-1070. Date of Electronic Publication: 2021 Oct 21. - Publication Year :
- 2021
-
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.<br /> (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Details
- Language :
- English
- ISSN :
- 2662-1347
- Volume :
- 2
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Nature cancer
- Publication Type :
- Academic Journal
- Accession number :
- 35121883
- Full Text :
- https://doi.org/10.1038/s43018-021-00261-1