Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jun 19;2(2):161-177.
doi: 10.20517/cdr.2018.27. eCollection 2019.

Emerging targets in cancer drug resistance

Shashank Kumar  1 , Prem Prakash Kushwaha  1 , Sanjay Gupta  2   3   4   5   6
Affiliations
Review

Emerging targets in cancer drug resistance

Shashank Kumar et al. Cancer Drug Resist. .

Abstract

Drug resistance is a complex phenomenon that frequently develops as a failure to chemotherapy during cancer treatment. Malignant cells increasingly generate resistance to various chemotherapeutic drugs through distinct mechanisms and pathways. Understanding the molecular mechanisms involved in drug resistance remains an important area of research for identification of precise targets and drug discovery to improve therapeutic outcomes. This review highlights the role of some recent emerging targets and pathways which play critical role in driving drug resistance.

Keywords: Drug resistance; FOXO transcription factors; Keap1-Nrf2; MIEN1; PI3K-Akt; annexins; focal adhesion kinases; gene splicing; microRNA; sphingolipids; transforming growth factor-β.

PubMed Disclaimer

Conflict of interest statement

All authors declared that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanism of cisplatin resistance. Ligand binding to transforming growth factor beta (TGF-β) receptor initiates intracellular signaling through Smad protein complex (SPC). In the nucleus, SPC bind with the DNA binding domain which results in expression of p21/Waf1 and Nrf2 gene. p21/Waf1 and Nrf2 gene products tightly regulate glutathione metabolism. Cisplatin enters cells by passive diffusion. At low chloride ion concentration, the chloride ion of cisplatin is replaced with water molecules and forms activated cisplatin (aquation). Activated cisplatin enters the nucleus and results into the transcription of genes involved in anticancer activity. Glutathione conjugation with cisplatin hinders its nuclear translocation and thereby its chemo-preventive potential resulting into cisplatin resistance
Figure 2
Figure 2
Keap1-Nrf2 signaling pathway in cancer drug resistance. Interaction of Keap1 molecules to Nrf2 protein is followed by Cul3-based E3 ligase complex mediated Nrf2 polyubiquitylation results into its proteasomal degradation. In the absence of Keap1 molecules, Nrf2 freely enters in the nucleus and transcribes its target genes in association with other nuclear factors. PI3K/Akt/TNF-α/NF-κB pathway directly phosphorylates FOXO3a proteins and directs them for ubiquitination and proteasomal degradation. Normally, FOXO3a proteins inhibits FOXM1 function and represses FOXM1 targeted transcription. FOXO3a protein also transcribes Keap1 genes. Absence of FOXO3a protein results in to downregulation of Keap1 mRNA and FOXM1 targeted genes
Figure 3
Figure 3
EGFR/PI3K/MAPK/ERK1/2-FOXO3a pathways in cancer drug resistance. Overexpression of MIEN1 and ABCG2/ABCB1 initiates the cisplatin resistance by targeting Akt/RelA/p50 and efflux of cisplatin respectively. MIEN1 targets Akt/RelA/p50 and induces overexpression of the anti-apoptotic proteins. Akt protein activated by MIEN1 inhibits FOXO3a function. Together, P38 and JNK phosphorylate FOXO3a protein which results in to its ubiquitination and proteasomal degradation. MEK/ERK pathway phosphorylates FOXM1 proteins which results in to translocation of these proteins inside the nucleus. Phosphorylated FOXM1 transcribes several genes which positively involves in drug resistance
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, McLennan MT, et al. Nitrogen mustard therapy: the use of methyl-bis(β-chloroethyl) amine hydrochloride and tris(\sb-chlorethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia, and certain allied and miscellaneous disorders. JAMA. 1946;132:126–32. doi: 10.1001/jama.1946.02870380008004. - DOI - PubMed
    1. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13:714–26. doi: 10.1038/nrc3599. - DOI - PubMed
    1. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27. doi: 10.1146/annurev.med.53.082901.103929. - DOI - PubMed
    1. Glavinas H, Krajcsi P, Cserepes J, Sarkadi B. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv. 2004;1:27–42. doi: 10.2174/1567201043480036. - DOI - PubMed
    1. McCubrey JA, Abrams SL, Fitzgerald TL, Cocco L, Martelli AM, et al. Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis. Adv Biol Regul. 2015;57:75–101. doi: 10.1016/j.jbior.2014.09.016. - DOI - PubMed

LinkOut - more resources