Cancer Drug Resistance: A Brief Overview from a Genetic Viewpoint

Abstract

Cancer drug resistance leading to therapeutic failure in the treatment of many cancers encompasses various mechanisms and may be intrinsic relying on the patient's genetic makeup or be acquired by tumors that are initially sensitive to cancer drugs. All in all, it may be responsible for treatment failure in over 90 % of patients with metastatic cancer. Cancer drug resistance, in particular acquired resistance, may stem from the micro-clonality/micro-genetic heterogeneity of the tumors whereby, among others, the following mechanisms may entail resistance: altered expression of drug influx/efflux transporters in the tumor cells mediating lower drug uptake and/or greater efflux of the drug; altered role of DNA repair and impairment of apoptosis; role of epigenomics/epistasis by methylation, acetylation, and altered levels of microRNAs leading to alterations in upstream or downstream effectors; mutation of drug targets in targeted therapy and alterations in the cell cycle and checkpoints; and tumor microenvironment that are briefly reviewed.

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

“…In conclusion, it remains to be fully ascertained whether JAK2 mutations may considered as 'driver mutations' for MPNs, or if they can act as 'passenger mutations' which may change place with the former and have 'driver' functions (24).…”

“…Although it is possible to identify one of these mutations in the majority of the BCR/ ABL-negative disorder patients, there are unidentified genetic defects in approximately 10-15% of cases, predominantly of ET and PMF and, furthermore, those mutations cannot fully explain the phenotypic heterogeneity of PN-MPNs nor the susceptibility of progression to myelofibrosis, acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS) (16). In addition, the cellular and molecular mechanisms involved in the pathophysiology of MPNs have not yet been fully clarified (16,(19)(20)(21)(22)(23)(24)(25)(26). It is well known that hematopoietic cytokine receptor signaling is largely mediated by JAKs, a family of tyrosine kinases, and their downstream transcription factors, termed signal transducer and activator of transcription (STAT).…”

The context of prostate cancer genomics in personalized medicine

“…Drug resistance is a significant challenge associated with cancer therapy (62,63,65,69). A cancer cell with alterations in drug targeting sites, activation of alternative survival pathways and altered expression of drug influx/efflux transporters may result in the development of a resistant generation of cancer cells.…”

The Molecular Connections between Lung and Pancreatic Cancer Metastases: are we not seeing the Forest for the Trees?

“…Likewise, the Hh pathway crosstalks with other pathways such as TGFβ and IGF-R. If TGFβ and IGF-R pathways are abrogated, their downstream targets are still activated by Hh [160,161]. Thus, genetic redundancy fortifies natural selection for cell survival (drug resistance) [162].…”

“…Stochastic variations in SNPs, genomic rearrangements, epigenetic alterations, LOH, haploinsufficiency, and so forth, are thought to influence tumor heterogeneity and interpatient regularity [203]. Hh, NOTCH, WNT, and CXCR4/ CXCL12 transmute genomic and epigenomic programming into actionable tumor progression [121,161,[204][205][206][207]. Without an understanding of the divergent molecular TSIs that impose on cancer behavior, a one-size-fits-all therapeutic approach in treating LC and PC patients has a inherent probability of failure [208][209][210].…”