scholarly journals FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Carlos J Diaz Osterman ◽  
Duygu Ozmadenci ◽  
Elizabeth G Kleinschmidt ◽  
Kristin N Taylor ◽  
Allison M Barrie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Chemotherapy Resistance ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Platinum Resistance ◽  
Cancer Resistance ◽  
Copy Number Alterations ◽  
Neo Adjuvant Chemotherapy ◽  
Platinum Chemotherapy ◽  
Repair Genes

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.

scholarly journals FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

2019 ◽  
Author(s):  
Carlos J. Díaz Osterman ◽  
Duygu Ozmadenci ◽  
Elizabeth G. Kleinschmidt ◽  
Kristin N. Taylor ◽  
Allison M. Barrie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Gene Copy ◽  
Platinum Resistance ◽  
List Type ◽  
High Grade ◽  
Cancer Resistance ◽  
Platinum Chemotherapy

AbstractGene 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-β-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encodingKRAS,MYCandFAK, 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 apoptosisin vitroandin vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/β-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.Graphical SummaryKey PointsHigh grade serous ovarian carcinoma tumors containPTK2(FAK) 8q24.3 gains associated with prognostic differences.KMF, a new murine ovarian cancer model withK-Ras,Myc, andFAK gene gains and intrinsic platinum resistance.FAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.FAK facilitates a β-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.FAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance.

scholarly journals Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment

2018 ◽  
Vol 25 (5) ◽  
pp. R303-R318 ◽  
Author(s):  
Belinda van Zyl ◽  
Denise Tang ◽  
Nikola A Bowden
Keyword(s):  
Ovarian Cancer ◽  
Survival Rates ◽  
Chemotherapy Resistance ◽  
Initial Response ◽  
Disease Recurrence ◽  
Future Research ◽  
Platinum Resistance ◽  
Platinum Resistant ◽  
New Treatments ◽  
Platinum Chemotherapy

Ovarian cancer has poor survival rates due to a combination of diagnosis at advanced disease stages and disease recurrence as a result of platinum chemotherapy resistance. High-grade serous ovarian cancer (HGSOC), the most common ovarian cancer subtype, is conventionally treated with surgery and paclitaxel/carboplatin combination chemotherapy. Initial response rates are 60–80%, but eventually the majority of patients become platinum-resistant with subsequent relapses. Extensive research on individual biomarkers of platinum resistance has revealed many potential targets for the development new treatments. While this is ongoing, there are also epigenetic, DNA repair, genome and immune changes characterised in platinum-resistant HGSOC that can be targeted with current therapies. This review discusses biomarkers of platinum chemotherapy resistance in ovarian cancer with a focus on biomarkers that are targetable with alternative treatment combinations to those currently used. After decades of research focused on elucidating the biological cause of platinum resistance, future research needs to focus on using this knowledge to overcome resistance for patients with ovarian cancer.

Gene Copy Number Alterations Involving CSMD1 in Oral Squamous Cell Carcinoma

2005 ◽  
Vol 133 (2) ◽  
pp. P141-P142
Author(s):  
A SPARANO ◽  
M KUMAR ◽  
K QUESNELLE ◽  
M BROSE
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Copy Number Alterations

scholarly journals A Bar Code of Selected Gene Copy Number Alterations is Associated with Disease-Free Survival in Stage Ii-Iii Microsatellite Stable (Mss) Colon Cancer

2014 ◽  
Vol 25 ◽  
pp. iv193
Author(s):  
F. Di Fiore ◽  
L. Armengol-Debeir ◽  
F. Blanchard ◽  
C. Chapusot ◽  
B. Tournier ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
Free Survival ◽  
Bar Code ◽  
Disease Free

scholarly journals Comprehensive Profiling of Gene Copy Number Alterations Predicts Patient Prognosis in Resected Stages I–III Lung Adenocarcinoma

2019 ◽  
Vol 9 ◽  
Author(s):  
Xiaohong Han ◽  
Qiaoyun Tan ◽  
Sheng Yang ◽  
Junling Li ◽  
Jianping Xu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
Patient Prognosis

Analysis of gene copy number alterations by multiplex ligation-dependent probe amplification in columnar cell lesions of the breast

2014 ◽  
Vol 37 (2) ◽  
pp. 147-154 ◽  
Author(s):  
Anoek H. J. Verschuur-Maes ◽  
Cathy B. Moelans ◽  
Peter C. de Bruin ◽  
Paul J. van Diest
Keyword(s):  
Copy Number ◽  
Gene Copy Number ◽  
Columnar Cell ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
Columnar Cell Lesions ◽  
Dependent Probe

EGFR gene copy number alterations are not a useful screening tool for predicting EGFR mutation status in lung adenocarcinoma

Pathology ◽  
2014 ◽  
Vol 46 (1) ◽  
pp. 32-36
Author(s):  
Prudence A. Russell ◽  
Y.U. Yong ◽  
D.O. Hongdo ◽  
Timothy D. Clay ◽  
Melissa M. Moore ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Screening Tool ◽  
Egfr Mutation ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
Mutation Status ◽  
Egfr Gene

scholarly journals Oligonucleotide array-CGH reveals cryptic gene copy number alterations in karyotypically normal acute myeloid leukemia

Leukemia ◽  
2007 ◽  
Vol 21 (3) ◽  
pp. 571-574 ◽  
Author(s):  
A Tyybäkinoja ◽  
E Elonen ◽  
K Piippo ◽  
K Porkka ◽  
S Knuutila
Keyword(s):  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Array Cgh ◽  
Gene Copy Number ◽  
Oligonucleotide Array ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
Acute Myeloid
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