Upregulated FGFR1 expression is associated with the transition of hormone-naive to castrate-resistant prostate cancer

Armstrong, Kelly; Ahmad, Imran; Kalna, Gabriela; Tan, Ss.S.; Edwards, Joanne; Robson, Craig; Leung, Hing Y.

doi:10.1038/bjc.2011.367

Cited by 27 publications

(29 citation statements)

References 26 publications

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“…Interestingly, FGFR1 amplification may be associated with anti-androgen resistance as well. In prostate cancer, overexpression of FGFR1 has been associated with increased risk of developing castrate-resistant prostate cancer when FGFR1 expression is elevated in hormone-naïve tumors, higher levels in castrate-resistant versus hormone-naïve tumors, as well as shorter time to death in castrate resistant tumors [30]. …”

Section: Discussionmentioning

confidence: 99%

FGFR1 Amplification in Squamous Cell Carcinoma of The Lung

Heist

Mino‐Kenudson

Sequist

et al. 2012

Journal of Thoracic Oncology

170

112

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Introduction Amplification of FGFR1 has been reported in squamous cell lung carcinoma and may be a molecular target for therapy. Little is known, however, about the clinical and demographic correlates of FGFR1 amplification. Methods The study is an institutional review board-approved retrospective analysis of 226 patients with squamous cell lung cancer seen at the Massachusetts General Hospital (MGH) from 2005–2011. Clinical and demographic characteristics were obtained on all patients, as well as treatment details including surgery, radiation, and chemotherapy, and overall survival. FISH was performed for FGFR1 on formalin fixed paraffin-embedded tumor tissue. Clinical genotyping results were also reviewed where available. Results 37 of 226 (16%) patients with squamous cell lung cancer were positive for amplification using a definition of amplification of a gene to copy number control ratio >/= 2.2. FGFR1 amplification status was not associated with age, sex, stage, histologic subtype within squamous cell, smoking history or pack-years of smoking. We found no significant difference in overall survival by FGFR1 amplification status as a whole; in the advanced stage subset, our findings are inconclusive due to the small sample size. Conclusions FGFR1 amplification was found in 16% of a clinical cohort of squamous cell lung cancer patients. The lack of any specific clinicodemographic features that correlates with FGFR1 amplification suggests that all squamous cell patients should be tested for this genomic change.

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Section: Discussionmentioning

confidence: 99%

FGFR1 Amplification in Squamous Cell Carcinoma of The Lung

Heist

Mino‐Kenudson

Sequist

et al. 2012

Journal of Thoracic Oncology

170

112

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“…FGFR1 up-regulation combined with promoter hypomethylation was previously described in rhabdomyosarcomas [58]. Other studies described that FGFR1 increased levels is a common feature in different tumor types, such as glioblastoma [59] and cancers of the breast [60], lung [61], prostate [62], bladder [63], ovarian [64], colorectal [27] and HNSCC [29,65,66]. FGFR1 is involved in resistance mechanisms against EGFR inhibitors [27,[46][47][48], such as cetuximab and gefitinib.…”

Section: Discussionmentioning

confidence: 87%

Integrated time course omics analysis distinguishes immediate therapeutic response from acquired resistance

Stein-O’Brien

Kagohara

et al. 2017

Preprint

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BACKGROUND: Targeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients' treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. To determine the dynamics of these molecular changes, we obtained high throughput omics data weekly during the development of cetuximab resistance in a head and neck cancer in vitro model. RESULTS:An unsupervised algorithm, CoGAPS, was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmapbased visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically. CONCLUSIONS:Genes with epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize resistance. These genes include FGFR1, which was associated with EGFR inhibitor resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. Our findings provide a relevant towards better understanding of the time course progression of changes resulting in acquired resistance to targeted therapies. This is an important contribution to the development of alternative treatment strategies that would introduce new drugs before the resistant phenotype develops.

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“…Multiple RTK growth factor signaling pathways including EGFR 26,27 , IGF-1R 28,29 , FGFR 30 , PDGFR 31,32 , and HGFR/c-MET 33-35 pathways have been investigated extensively in prostate cancer progression due to their activation of the PI3K-AKT and RAS-MAPK pathways. Combined loss of PTEN with activation of the RAS-MAPK pathway can cooperate to induce epithelial to mesenchymal transition (EMT) and metastases 36 .…”

Section: Introductionmentioning

confidence: 99%