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Cellular Origins of EGFR-driven Lung Cancer Cells Determines Sensitivity to Therapy

ABSTRACT: Cellular Origins of EGFR-driven Lung Cancer Cells Determines Sensitivity to Therapy

PROVIDER: PRJNA747984 | ENA |

REPOSITORIES: ENA

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Cellular Origins of EGFR-driven Lung Cancer Cells Determines Sensitivity to Therapy

Project description:The purpose of this research is to study the cellular origins of EGFR-mutant lung cancers and their responses to therapies. We discovered that activation of EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can be originated from alveolar type 2 (AT2) cells or bronchioalveolar stem cells (BASCs), but not basal cells or club cells of the trachea. Crucially, the tumoroids with different cell-of-origins or epigenetic states had distinct drug vulnerabilities.

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Cellular Origins of EGFR-Driven Lung Cancer Cells Determine Sensitivity to Therapy.

Project description:Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells, but not basal cells or club cells of the trachea. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions.

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IRS1 phosphorylation determines a heritable probability of cancer cells to persist during EGFR inhibition therapy

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.

2021-06-22 | PXD026834 | Pride

Selective polyprotein processing determines norovirus sensitivity to Trim7

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

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.

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

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

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Expression comparison of mutant EGFR-driven gliomas with relapse tumors upon mutant EGFR ablation

Project description:To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Genetic suppression of EGFR* induction led to significant tumor regression and prolonged survival. But in spite of the initial response, the tumors relapsed invariably and propagated independent of EGFR*. We used microarrys to directly compare geen expression of control and relapse tumors and identified gene sets specifically activated in relapse tumors. Control and relasped glioma samples upon mutant EGFR extinction were selected for RNA extraction and hybridization on Affymetrix microarrays.

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Biochemical and Structural Basif for Differential Inhibitor Sensitivity of EGFR with Distinct Exon 19 Mutaions

Project description:Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). We studied structural basis of differential TKI sensitivity among EGFR exon 19 mutants by HDX-MS.

2023-03-11 | PXD037374 | Pride

An EGFR-mutation signature reveals features of the EGFR-dependent phenotype and identifies MACC1 as an EGFR-associated regulator of MET.

Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.

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