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Review
. 2024 Feb 12;22(1):109.
doi: 10.1186/s12964-023-01302-1.

Unveiling the mechanisms and challenges of cancer drug resistance

Sameer Ullah Khan #  1   2   3 , Kaneez Fatima #  4   5 , Shariqa Aisha  4   5 , Fayaz Malik  6   7
Affiliations
Review

Unveiling the mechanisms and challenges of cancer drug resistance

Sameer Ullah Khan et al. Cell Commun Signal. .

Abstract

Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance. Video Abstract.

Keywords: Apoptosis; Autophagy; Cancer stem cells; Drug resistance; Immune cells; Multi-drug resistance.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Cancer cell and drug-resistant cancer cell response to an anti-cancer drug. Chemotherapeutic drugs are effective on cancer cells as they enter into the cells and activate various anti-cancer pathways, leading to DNA damage and cell death. In resistant cells, cancer cells modulate drugs or produce a barrier to them which collectively resulted in decreasing their effectivity on cancer cells. Figure created with ChemBioDraw Ultra 14.0
Fig. 2
Fig. 2
Role of CSC in drug resistance and relapse by altering its microenvironment and modifying the host immune system. CSCs are resistant to various therapies compared to cancer cells by activating various survival pathways and also changing their microenvironment like increasing autophagy as well as secreting various chemokines and cytokines which in turn cause drug resistance. Figure created with BioRender.com
Fig. 3
Fig. 3
pH change and cellular organelle's role in drug resistance. Resistant Cancer cells change extracellular (ECM) as well as intracellular (cytosol, subcellular organelles) pH according to their requirement thus activating various pathways which cause metabolic, genetic, epigenetic rewiring to support their survival, metastasis, and drug resistance. Figure created with ChemBioDraw Ultra 14.0
Fig. 4
Fig. 4
Cancer cells hijack cellular organelles for their benefit. Cancer cells respond to drugs by decreasing ROS production( by peroxisomes), increasing drug efflux pumps(on the membrane of organelles and cells), drug-metabolizing enzyme(ER-CYP) and sequestering drugs (by lysosome and Golgi). Figure created with BioRender.com
Fig. 5
Fig. 5
Exosome-mediated drug resistance: Drug-resistant tumor cells can connect with drug-sensitive tumor cells through the exchange of exosomes. Exosomes can transport proteins (such as drug-efflux pumps) and other critical components involved in drug resistance. Mesenchymal stem cells (MSC)-derived exosomes stimulate calcium-dependent protein kinases and Ras/Raf/MEK/ERK kinase pathways which in turn activate multiple drug efflux pumps. Figure created with BioRender.com
Fig. 6
Fig. 6
Depicting the resistance mechanisms of the different drugs at the proteomic level. Figure created with BioRender.com
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