Advances and challenges in targeting FGFR signalling in cancer

Babina, Irina S.; Turner, Nicholas C.

doi:10.1038/nrc.2017.8

Cited by 557 publications

(602 citation statements)

References 162 publications

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“…Approved targeted therapies are available for variants in receptor tyrosine kinases, such as EGFR (also termed HER1), ERBB2 (also termed HER2), PDGFRA, KIT, ALK, and JAK2 that are commonly mutated in various cancers. Furthermore, targeting activating mutations, amplifications, or gene fusion events of FGFRs represents promising therapeutic opportunities for various solid tumors with multiple clinical trials currently ongoing [104].…”

Section: Genetic Biomarkers In the Somatic Cancer Genomementioning

confidence: 99%

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

Lauschke

Milani

Ingelman‐Sundberg

2017

AAPS J

109

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Abstract.Much of the inter-individual variability in drug efficacy and risk of adverse reactions is due to polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics or immunological responses. Pharmacogenetic research has identified a multitude of gene-drug response associations, which have resulted in genetically guided treatment and dosing decisions to yield a higher success rate of pharmacological treatment. The rapid technological developments for genetic analyses reveal that the number of genetic variants with importance for drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to millions of rare mutations. Here, we review the evolutionary background of genetic polymorphisms in drugmetabolizing enzymes, provide some important examples of current use of pharmacogenomic biomarkers, and give an update of germline and somatic genome biomarkers that are in use in drug development and clinical practice. We also discuss the current technology development with emphasis on complex genetic loci, review current initiatives for validation of pharmacogenomic biomarkers, and present scenarios for the future taking rare genetic variants into account for a true personalized genetically guided drug prescription. We conclude that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology. However, the routine use of pharmacogenomic biomarkers in clinical practice in other therapeutic areas is currently sparse and the prospects of its future implementation are being scrutinized by different international consortia.

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Section: Genetic Biomarkers In the Somatic Cancer Genomementioning

confidence: 99%

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

Lauschke

Milani

Ingelman‐Sundberg

2017

AAPS J

109

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“…Fibroblast growth factor (FGF) family and their four receptor tyrosine kinases (FGFR1,2,3,4) cover an essential role in many physiologic processes such as tissue homeostasis and repair, embryogenesis, inflammation, and wound healing. However, the amplification of their expression was found in different kind of cancers such as breast, gastric, cervical, oral, or bladder cancer . Recently, the combination composed of HDAC6 and TK inhibitors was proven to be effective against breast cancer, suggesting the possible development of hybrid compounds able to interact with both targets .…”

Section: The Mtdl Approachmentioning

confidence: 94%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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“…Notably, a phase I program that was conducted at The University of Texas MD Anderson Cancer Center showed that patients who received therapy that matched with the alteration (n = 143) showed a higher objective response rate (12% vs 5%; P < .0001), longer PFS (median, 3.9 vs 2.2 months; P = .001), and longer overall survival (median, 11.4 vs 8.6 months; P = .04) compared with treatment without matching (n = 236) . Recently, genomic alterations in druggable targets, such as EGFR, BRAF, RET, ALK, ROS1, CDK4/6, MET, FGFR, were included in trials to match patients to therapies . Taken together, comprehensive genomic profiling by clinical sequencing could categorize cancer patients based on genetic alterations and therapy could be provided according to the genetic alteration, thus implementing cancer precision medicine.…”

Section: Genome‐based Medicine That Leads To Cancer Precision Medicinementioning

confidence: 99%

Breast cancer: The translation of big genomic data to cancer precision medicine

2017

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Cancer is a complex genetic disease that develops from the accumulation of genomic alterations in which germline variations predispose individuals to cancer and somatic alterations initiate and trigger the progression of cancer. For the past 2 decades, genomic research has advanced remarkably, evolving from single‐gene to whole‐genome screening by using genome‐wide association study and next‐generation sequencing that contributes to big genomic data. International collaborative efforts have contributed to curating these data to identify clinically significant alterations that could be used in clinical settings. Focusing on breast cancer, the present review summarizes the identification of genomic alterations with high‐throughput screening as well as the use of genomic information in clinical trials that match cancer patients to therapies, which further leads to cancer precision medicine. Furthermore, cancer screening and monitoring were enhanced greatly by the use of liquid biopsies. With the growing data complexity and size, there is much anticipation in exploiting deep machine learning and artificial intelligence to curate integrative “−omics” data to refine the current medical practice to be applied in the near future.

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Advances and challenges in targeting FGFR signalling in cancer

Cited by 557 publications

References 162 publications

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Breast cancer: The translation of big genomic data to cancer precision medicine

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