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Acquired resistance to entrectinib or crizotinib drives differential gene expression in ROS1+ NSCLC

ABSTRACT: Acquired resistance to entrectinib or crizotinib drives differential gene expression in ROS1+ NSCLC

PROVIDER: PRJNA886729 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21789604_1.fastq.gz	Fastqsanger.gz
	SRR21789604_2.fastq.gz	Fastqsanger.gz
	SRR21789605_1.fastq.gz	Fastqsanger.gz
	SRR21789605_2.fastq.gz	Fastqsanger.gz
	SRR21789606_1.fastq.gz	Fastqsanger.gz

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Acquired resistance to entrectinib or crizotinib drives differential gene expression in ROS1+ NSCLC

Project description:Utilizing primary, patient tumor-derived ROS1+ NSCLC cell lines, we derived TKI-resistant cell lines by chronic exposure to TKI in the media. One of our parental, ROS1 TKI-sensitive cell lines harbors a TPM3-ROS1 fusion (CUTO28) and the other harbors a CD74-ROS1 fusion (CUTO37). Entrectinib-resistant (-ER) and crizotinib-resistant (-CR) lines are so named when they are stably proliferating at 500nM concentration of the respective TKI. We sought to investigate transcriptome changes with acquired resistance to entrectinib or crizotinib.

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Project description:Despite the initial benefit of tyrosine kinase inhibitors targeting ROS1 fusion kinase in non-small cell lung cancer, the complete responses are rare and resistance ultimately develops from residual tumor cells. Although several acquired resistance mechanisms after disease progression have been reported, the adaptative resistance mechanism that contributes to residual diseases before the onset of acquired resistance is less clear. Cellular adaption through the signaling rewiring under primary oncogene inhibition is considered a major mechanism contributing to residual disease. To explore the rapid signaling reprogramming under acute ROS1 inhibition, we treated a panel of ROS1 fusion-positive cells, mostly derived in our lab, with crizotinib for 24 hours and profiled transcriptional changes by RNA-seq. Understanding the molecular mechanism that supports residual disease could help us better target and eliminate drug-tolerant cells, thus improving the responses to ROS1 targeted therapies.

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Project description:The non-small cell lung cancer (NSCLC) cell line HCC827 harbors an activating EGFR mutation (exon 19 deletion) that confers sensitivity to the FDA-approved EGFR inhibitor erlotinib. By applying the ClonTracer barcoding system, we were able to show the presence of pre-existing sub-populations in HCC827 that contribute to erlotinib resistance. Prior studies implicated that MET amplification confers resistance to erlotinib in this cell line. Therefore we examined the effects of the c-Met inhibitor crizotinib on the barcoded HCC827 population when treated either sequentially or simultaneously with both inhibitors. Despite the significant reduction in barcode complexity, the erlotinib/crizotinib combination treatment failed to eradicate all of the resistant clones implying the presence of an erlotinib/crizotinib dual resistant subpopulation. We performed transcriptome profiling (RNA-seq) to elucidate the potential resistance mechanisms of the dual resistant subpopulation in comparison to vehicle-treated or single agent erlotinib-resistant HCC827 cell populations as controls. mRNA profiling of the subpopulations of human NSCLC cell line HCC827 that contribute to EGFR inhibitor erlotinib and MET inhibitor crizotinib resistance

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