Table 4.

Overview of Drug Resistance Mechanisms and Genes in Cancer Stem Cells

Drug	Resistance Gene(s)	Mechanism of Resistance	Cancer Type	Associated Cancer Stem Cell Characteristics	References
Doxorubicin	ABCB1 (P-glycoprotein)	Efflux pump expels drug from cells, reducing intracellular drug concentration	Breast, Ovarian, Leukemia	CSCs overexpress ABCB1, leading to multidrug resistance (MDR)	[39, 277–279]
Cisplatin	ERCC1, XPF	Enhanced DNA repair capacity through NER (nucleotide excision repair) mechanism	Ovarian, Lung	CSCs exhibit high DNA repair and survival capabilities	[280–284]
Imatinib	BCR-ABL	Point mutations in the kinase domain prevent drug binding	Chronic Myeloid Leukemia (CML)	CSCs harbor mutations in the BCR-ABL fusion protein	[285–289]
Methotrexate	DHFR (Dihydrofolate Reductase)	Gene amplification increases DHFR enzyme levels, bypassing methotrexate inhibition	Breast, Leukemia	CSCs show survival due to DHFR amplification	[290–294]
5-Fluorouracil (5-FU)	TYMS (Thymidylate Synthase)	Overexpression or mutations reduce the drug’s ability to inhibit DNA synthesis	Colorectal, Gastric	CSCs upregulate TYMS, resulting in enhanced survival	[295–298]
Paclitaxel	TUBB (Beta-tubulin)	Beta-tubulin mutations alter microtubule stability, reducing drug binding	Breast, Lung, Ovarian	CSCs show alterations in tubulin that lead to resistance	[299–304]
Vincristine	ABCC1 (MRP1)	Efflux pump reduces intracellular concentration of the drug	Leukemia, Neuroblastoma	CSCs overexpress ABCC1 leading to efflux-mediated resistance	[248, 305–310]
Temozolomide	MGMT (O6-Methylguanine-DNA Methyltransferase)	MGMT repairs DNA by removing drug-induced lesions	Glioblastoma	CSCs exhibit high MGMT levels, contributing to therapy resistance	[112, 311–317]
Gefitinib/Erlotinib	EGFR (Epidermal Growth Factor Receptor)	Mutations (e.g., T790M) reduce drug-binding efficacy	Non-small cell lung cancer (NSCLC)	CSCs harbor EGFR mutations that prevent efficient drug inhibition	[318–322]
Sorafenib	RAF, MEK, ERK (MAPK Pathway)	Activation of MAPK signaling pathway leads to compensatory survival pathways	Hepatocellular carcinoma	CSCs bypass drug effect via alternative signaling pathway activations	[323–327]
Oxaliplatin	MLH1, MSH2 (Mismatch Repair Genes)	Deficient mismatch repair reduces apoptosis triggered by DNA damage	Colorectal	CSCs exhibit mismatch repair deficiency (MSI-high), evading apoptosis	[22, 328–333]
Carboplatin	BRCA1/2 (Breast Cancer Genes)	Secondary mutations restore BRCA function, enabling homologous recombination repair	Ovarian, Breast	CSCs restore BRCA functionality, promoting drug resistance	[334–339]
Docetaxel	TUBB3 (Class III Beta-tubulin)	Overexpression of TUBB3 decreases microtubule binding affinity, leading to resistance	Prostate, Breast, Lung	CSCs show altered microtubule dynamics via TUBB3 expression	[340–343]
Tamoxifen	ESR1 (Estrogen Receptor)	ESR1 mutations alter estrogen receptor function, reducing the efficacy of anti-estrogen drugs	Breast	CSCs harbor ESR1 mutations, leading to tamoxifen resistance	[244, 344–348]
Trastuzumab	HER2 (Human Epidermal Growth Factor Receptor 2)	Mutations in HER2 prevent effective trastuzumab binding	HER2-positive Breast Cancer	CSCs expressing altered HER2 maintain resistance to trastuzumab	[349–352]