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Farnesyltransferase inhibition overcomes the adaptive resistance to targeted therapies in oncogene-addicted non-small cell lung cancer

ABSTRACT: Farnesyltransferase inhibition overcomes the adaptive resistance to targeted therapies in oncogene-addicted non-small cell lung cancer

PROVIDER: PRJNA1044045 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26919203_1.fastq.gz	Fastqsanger.gz
	SRR26919203_2.fastq.gz	Fastqsanger.gz
	SRR26919204_1.fastq.gz	Fastqsanger.gz
	SRR26919204_2.fastq.gz	Fastqsanger.gz
	SRR26919205_1.fastq.gz	Fastqsanger.gz

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Farnesyltransferase inhibition overcomes the adaptive resistance to targeted therapies in oncogene-addicted non-small cell lung cancer II

Project description:Farnesyltransferase inhibition overcomes the adaptive resistance to targeted therapies in oncogene-addicted non-small cell lung cancer II

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Rhabdomyosarcomas are oncogene addicted to the activation of AVIL

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Farnesyltransferase inhibition overcomes the adaptive resistance to targeted therapies in oncogene-addicted non-small cell lung cancer

Project description:Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we used the FUCCI (fluorescence ubiquitination cell cycle indicator) system to perform real-time monitoring of the cell cycle dynamics the EGFR-mutant NSCLC cell line HCC4006, which was previously subcloned to minimize the presence of potential pre-existing resistant cells. We performed scRNAseq on G1 (red) and S/G2 (green) cells sorted from untreated (DMSO), osimertinib-treated and osimertinib+tipifarnib-treated cells to identify molecular mechanisms implicated in the adaptive response to TT and the sensitivity of drug-tolerant cells to tipifarnib.

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Farnesyltransferase inhibition overcomes the adaptive resistance to targeted therapies in oncogene-addicted non-small cell lung cancer II

Project description:Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we performed transcriptomic profiling by RNAseq in a panel of EGFR-mutant NSCLC cell lines (PC9, HCC4006, H3255 and HCC827) that were previously subcloned to minimize the presence of potential pre-existing resistant cells. Cells were treated by either erlotinib (1 µM) or osimertinib (1 µM) for a short period (24h), until drug-tolerance (between 7 and 21 days), and until development of fully resistant proliferative cells (RPC).

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An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies

Project description:Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction remain largely unexplored. We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models and ex vivo non-small cell lung cancer patient organotypic cultures. We identified an ‘oncogene addiction phosphorylation signature’ (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments.

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Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction

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Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction

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Simvastatin overcomes resistance to tyrosine kinase inhibitors in patient-derived, oncogene-driven lung adenocarcinoma models

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