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FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [KMF parental, KMF clone KT13 (FAK-/-), KT13 + GFP-FAK, KT13 + GFP-FAK R454, and KT13 + deltaGSK beta-catenin]

ABSTRACT: Gene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-b-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/b-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE129098 | GEO | 2019/07/01

REPOSITORIES: GEO

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Project description:Changes in chromatin organization are associated with resistance to anti-cancer drugs, such as platinum-based chemotherapy used as the primary treatment of ovarian cancer. We have examined the genomic distribution of chromatin accessibility changes, and relationship to gene expression changes, occurring during acquisition of resistance in vivo of high grade serous ovarian cancer (HGSOC) patients and whether this associates with genomic DNA damage distribution. Using matched chemo-sensitive and chemo-resistant ovarian cell lines isolated from HGSOC patients before and following acquisition of clinical resistance to platinum-based chemotherapy, we have examined the relationship between chromatin accessibility by ATAC-seq, platinum-DNA adduct distribution by Pt-Exo-seq and gene expression by RNA-seq. We have correlated chromatin changes between the lines at gene promoters, CpG islands, enhancer sequences and other genomic regions with changes in gene expression and platinum-DNA adduct distribution. We observe chromatin conformation differences following acquisition of platinum-resistance, with the HGSOC resistant lines clustering together, separately from their respective sensitive counterparts. Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Super-enhancers, as defined by clusters of cis-regulatory elements, at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Genome-wide distribution of platinum adducts associates with the chromatin changes and distinguish sensitive from resistant lines. Regions incurring fewer platinum-adducts showed a significant reduction in accessibility the resistant HGSOC cell line PEO4 compared to the sensitive PEO1 counterpart. Surprisingly, regions showing increased damage in PEO4 had an even greater reduction in accessibility. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. In cell lines derived from patients following acquisition of clinical resistance to platinum-based chemotherapy, chromatin changes at super-enhancers correlate with gene expression changes in DNA repair pathways known to influence platinum sensitivity. Although cisplatin is a relatively non-specific DNA damaging agent, there are consistent differences in distribution of adducts between the matched sensitive and resistant ovarian cell lines, which is independent of the overall level of adducts formed.

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FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [KMF parental, KMF clone KT13 (FAK-/-), KT13 + GFP-FAK, KT13 + GFP-FAK R454, and KT13 + deltaGSK beta-catenin]

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