The emergence of drug resistance to targeted cancer therapies: Clinical evidence

Autoren

Ana Bela Sarmento-Ribeiro
Andreas Scorilas
Ana Cristina Gonçalves
Thomas Efferth
Ioannis P Trougakos

DOI

10.1016/j.drup.2019.100646

ISSN

1368-7646

Zeitschrift

Drug Resistance Updates

Sprache

en

Artikelnummer

100646

Paginierung

100646 - 100646

Datum der Veröffentlichung

2019

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.drup.2019.100646

Datum der Datenerfassung

2023

Titel

The emergence of drug resistance to targeted cancer therapies: Clinical evidence

Ausgabe der Zeitschrift

47

Data source: Crossref

Abstract

For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance develops and thus relapse emerges, resulting in increased mortality. Our attempts to understand the molecular basis underlying these drug resistance phenotypes in pre-clinical models and patient specimens revealed the extreme plasticity and adaptive pathways employed by tumor cells, being under sustained stress and extensive genomic/proteomic instability due to the applied therapeutic regimens. Subsequent efforts have yielded more effective inhibitors and combinatorial approaches (e.g. the use of specific pharmacologic inhibitors with immunotherapy) that exhibit synergistic effects against tumor cells, hence enhancing therapeutic indices. Furthermore, new advanced methodologies that allow for the early detection of genetic/epigenetic alterations that lead to drug chemoresistance and prospective validation of biomarkers which identify patients that will beneﬁt from certain drug classes, have started to improve the clinical outcome. This review discusses emerging principles of drug resistance to cancer therapies targeting a wide array of oncogenic kinases, along with hedgehog pathway and the proteasome and apoptotic inducers, as well as epigenetic and metabolic modulators. We further discuss mechanisms of resistance to monoclonal antibodies, immunomodulators and immune checkpoint inhibitors, potential biomarkers of drug response/drug resistance, along with possible new therapeutic avenues for the clinicians to combat devastating drug resistant malignancies. It is foreseen that these topics will be major areas of focused multidisciplinary translational research in the years to come.

Addresses

Laboratory of Oncobiology and Hematology and University Clinic of Hematology and Coimbra Institute for Clinical and Biomedical Research - Group of Environment Genetics and Oncobiology (iCBR/CIMAGO), Faculty of Medicine, University of Coimbra (FMUC), Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal; Hematology Department, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal. Electronic address: absarmento@fmed.uc.pt.

Autoren

Ana Bela Sarmento-Ribeiro
Andreas Scorilas
Ana Cristina Gonçalves
Thomas Efferth
Ioannis P Trougakos

DOI

10.1016/j.drup.2019.100646

eISSN

1532-2084

Externe Identifier

PubMed Identifier: 31733611

Funding acknowledgements

PlantUP-GR: MIS 5002803
Foundation for Science and Technology (FCT) Portugal: UID/NEU/04539/2013
Deutsche Forschungsgemeinschaft:
Deutsche Krebshilfe:
EU project TASCMAR: EU-H2020/634674
Hellenic GSRT projects BIOIMAGING-GR: MIS 5002755
COMPETE-FEDER: POCI-01-0145-FEDER-007440
Foundation for Science and Technology (FCT) Portugal: UID/NEU/04539/2019

Open access

false

ISSN

1368-7646

Zeitschrift

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

Schlüsselwörter

Humans
Neoplasms
Protein Kinase Inhibitors
Apoptosis
Drug Resistance, Neoplasm
Protein-Tyrosine Kinases
Hedgehog Proteins
Proteasome Inhibitors

Sprache

eng

Medium

Print-Electronic

Online publication date

2019

Paginierung

100646

Datum der Veröffentlichung

2019

Status

Published

Datum der Datenerfassung

2019

Titel

The emergence of drug resistance to targeted cancer therapies: Clinical evidence.

Sub types

Research Support, Non-U.S. Gov't
Review
Journal Article

Ausgabe der Zeitschrift

47

Data source: Europe PubMed Central

Abstract

For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance develops and thus relapse emerges, resulting in increased mortality. Our attempts to understand the molecular basis underlying these drug resistance phenotypes in pre-clinical models and patient specimens revealed the extreme plasticity and adaptive pathways employed by tumor cells, being under sustained stress and extensive genomic/proteomic instability due to the applied therapeutic regimens. Subsequent efforts have yielded more effective inhibitors and combinatorial approaches (e.g. the use of specific pharmacologic inhibitors with immunotherapy) that exhibit synergistic effects against tumor cells, hence enhancing therapeutic indices. Furthermore, new advanced methodologies that allow for the early detection of genetic/epigenetic alterations that lead to drug chemoresistance and prospective validation of biomarkers which identify patients that will beneﬁt from certain drug classes, have started to improve the clinical outcome. This review discusses emerging principles of drug resistance to cancer therapies targeting a wide array of oncogenic kinases, along with hedgehog pathway and the proteasome and apoptotic inducers, as well as epigenetic and metabolic modulators. We further discuss mechanisms of resistance to monoclonal antibodies, immunomodulators and immune checkpoint inhibitors, potential biomarkers of drug response/drug resistance, along with possible new therapeutic avenues for the clinicians to combat devastating drug resistant malignancies. It is foreseen that these topics will be major areas of focused multidisciplinary translational research in the years to come.

Date of acceptance

2019

Autoren

Ana Bela Sarmento-Ribeiro
Andreas Scorilas
Ana Cristina Gonçalves
Thomas Efferth
Ioannis P Trougakos

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/31733611

DOI

10.1016/j.drup.2019.100646

eISSN

1532-2084

Zeitschrift

Drug Resist Updat

Schlüsselwörter

Apoptosis
Autophagy
Epigenetic modulator
Hedgehog inhibitor
Immunotherapeutic agents
Kinase inhibitor
Metabolic modulator
Proteasome inhibitors
Apoptosis
Drug Resistance, Neoplasm
Hedgehog Proteins
Humans
Neoplasms
Proteasome Inhibitors
Protein Kinase Inhibitors
Protein-Tyrosine Kinases

Sprache

eng

Country

Scotland

Paginierung

100646

PII

S1368-7646(19)30043-3

Datum der Veröffentlichung

2019

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2020

Titel

The emergence of drug resistance to targeted cancer therapies: Clinical evidence.

Sub types

Journal Article
Research Support, Non-U.S. Gov't
Review

Ausgabe der Zeitschrift

47

Data source: PubMed

The emergence of drug resistance to targeted cancer therapies: Clinical evidence

Tools