Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer

Abstract

Cancer remains a leading cause of mortality globally and a major health burden, with chemotherapy often serving as the primary therapeutic option for patients with advanced-stage disease, partially compensating for the limitations of non-curative treatments. However, the emergence of chemotherapy resistance significantly limits its efficacy, posing a major clinical challenge. Moreover, heterogeneity of resistance mechanisms across cancer types complicates the development of universally effective diagnostic and therapeutic approaches. Understanding the molecular mechanisms of chemoresistance and identifying strategies to overcome it are current research focal points. This review provides a comprehensive analysis of the key molecular mechanisms underlying chemotherapy resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular drug metabolism, and the role of cancer stem cells (CSCs). We also examine specific causes of resistance in major cancer types and highlight various molecular targets involved in resistance. Finally, we discuss current strategies aiming at overcoming chemotherapy resistance, such as combination therapies, targeted treatments, and novel drug delivery systems, while proposing future directions for research in this evolving field. By addressing these molecular barriers, this review lays a foundation for the development of more effective cancer therapies aimed at mitigating chemotherapy resistance.

Keywords: Apoptosis evasion; Cancer stem cells; Chemotherapy resistance; Epigenetic modifications; Molecular mechanisms; Targeted therapy.

Fig. 1

General mechanisms of cancer chemoresistance. Upon exposure to chemotherapeutic agents, tumors initiate multiple mechanisms that mediate chemoresistance. Here, we delineate the molecular pathways involved in cancer chemoresistance, including: drug efflux, DNA damage repair, apoptosis evasion, epigenetic modifications, Altered Drug Metabolism, Cancer Stem Cells (CSCs)

Fig. 2

Apoptosis Evasion as a Mechanism of Chemoresistance. Chemotherapeutic intervention in tumor cells activates the intrinsic protective autophagy system. Concurrently, dysregulated expression and mutations in Bcl-2, IAP, and NF-κB family proteins impair chemotherapy-induced apoptosis in tumor cells. These factors collectively enable apoptosis evasion, leading to enhanced chemoresistance

Fig. 3

Overview of epigenetic modifications involved in cancer. (1) DNA methylation. Through the catalytic activity of DNMTs, cytosine residues are selectively methylated, producing 5-methylcytosine (5-mC). Methylation in promoter regions effectively downregulates the transcription of target genes, ultimately restricting the translation of mRNA into proteins. (2) Histone modifications. (a) (de)methylation. Histone methylation and demethylation, mediated by HMTs and HDMs, indirectly modulate chromatin accessibility and gene expression by altering the binding affinities of other epigenetic regulators. (b)(de)acetylation. Histone acetylation and deacetylation, catalyzed by HATs and HDACs, induce structural alterations in chromatin, thereby modulating gene expression. (c)(de)phosphorylation. Through the catalytic activities of PKs and PPs, histones undergo phosphorylation and dephosphorylation, facilitating rapid adjustments in chromatin structure and gene expression in response to cellular conditions and demands. (3) ncRNAs regulation. miRNA binds to the 3’ untranslated region (3’-UTR) of target mRNAs, typically leading to mRNA degradation or translational repression, which in turn reduces target protein expression. Conversely, lncRNA can act as a “miRNA sponge” by binding to miRNAs, preventing them from associating with their target mRNAs and thus promoting the expression of specific mRNAs

Fig. 4

Cancer stem cell model. Tumor tissues contain CSCs, a subpopulation with self-renewing properties. When chemotherapy is applied, typical cancer cells undergo apoptosis, yet CSCs evade these effects, leading to their survival and the possibility of treatment resistance

Fig. 5

Novel strategies to overcome chemoresistance in cancer. a Combination therapy. Combining chemotherapy with other modalities improves therapeutic outcomes. b Targeting the tumor microenvironment (TME). The TME serves as a formidable barrier that chemotherapeutic agents must overcome to achieve therapeutic efficacy. c Drug delivery systems. Various carriers can enhance drug delivery, addressing issues of poor targeting and increased toxicity. d Personalized medicine. Analyzing genetic composition allows for the customization of therapies to achieve the greatest treatment benefit