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IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy [Exp3]

ABSTRACT: We found that differential serine/threonine phosphorylation of the insulin receptor substrate 1 (IRS1) protein determines the chance to persist (CTP) of lung and of head and neck cancer cells under EGFR inhibition, both in vitro and in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178977 | GEO | 2021/08/09

REPOSITORIES: GEO

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IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy [Exp2]

Project description:We found that differential serine/threonine phosphorylation of the insulin receptor substrate 1 (IRS1) protein determines the chance to persist (CTP) of lung and of head and neck cancer cells under EGFR inhibition, both in vitro and in vivo.

2021-08-09 | GSE178976 | GEO

IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy [Exp1]

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Project description: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%. Importantly, 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 EGFR inhibition, both in vitro and in vivo. Indeed, the first-in-class IRS1 inhibitor NT219 was highly synergistic with anti-EGFR 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 novel rationally designed drug combinations.

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