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

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

PROVIDER: PRJNA1050239 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27158729_1.fastq.gz	Fastqsanger.gz
	SRR27158729_2.fastq.gz	Fastqsanger.gz
	SRR27158730_1.fastq.gz	Fastqsanger.gz
	SRR27158730_2.fastq.gz	Fastqsanger.gz
	SRR27158731_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

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

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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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Project description:Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, MARS-AVIL formed by chromosomal inversion in RMS. Suspecting that forming a fusion with a housekeeping gene may be one of the mechanisms to dysregulate an oncogene, we investigated AVIL expression and its role in RMS. We first showed that MARS-AVIL translates into an in-frame fusion protein, which is critical for the RMS cell tumorigenesis. Besides forming a gene fusion with the housekeeping gene, MARS, the AVIL locus is often amplified, and its RNA and protein expression is overexpressed in the majority of RMSs. Tumors with AVIL dysregulation exhibit evidence of oncogene addiction: silencing MARS-AVIL in cells harboring the fusion, or silencing AVIL in cells with AVIL overexpression, nearly eradicated the cells in culture, as well as inhibited in vivo xenograft growth in mice. Conversely, gain-of-function manipulations of AVIL led to increased cell growth and migration, enhanced foci formation in mouse fibroblasts, and most importantly transformed mesenchymal stem cells in vitro and in vivo. Mechanistically, AVIL seems to serve as a converging node functioning upstream of two oncogenic pathways, PAX3-FOXO1 and RAS, thus connecting two types of RMS associated with these pathways. Interestingly, AVIL is overexpressed in other sarcoma cells as well, and its expression correlates with clinical outcomes, with higher levels of AVIL expression being associated with worse prognosis. AVIL is a bona fide oncogene in RMS, and RMS cells are addicted to its activity.

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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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