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repair cross-complementing 1, whose increased levels has been linked to poor response to chemotherapy
in ovarian, gastric and non-small-cell lung carcinoma [61,62] . Cisplatin-treated testicular cancers showed
[63]
decreased levels of excision repair cross-complementing 1 .

EPIGENETIC MODIFICATIONS IN DRUG RESISTANCE
Alternative splicing
Splicing events after the post transcription process matures the mRNA to become respective functional
protein. Any deformities in these processes produce nonfunctional or mutated proteins resulting in cancer
initiation and development. Alternative splicing accomplishes coding region reshuffling and regulates mRNA
[64]
maturation . Defects in splicing mechanism lead to drug resistance against selected anticancer agents. BIM,
a type of BH3-only proteins belongs to the pro-apoptotic B-cell CLL/lymphoma 2 (BCL-2) protein family.
It play critical role in hematopoietic homeostasis, autoimmune disease restriction and cancer initiation.
[65]
BimEL, BimL and BimS are the three major BIM alternative splicing products . Studies provide evidence
that BIM alternative splicing molecules play a key role in drug resistance . Upregulated BIM proteins
[66]
facilitate tyrosine kinase inhibitors stimulated cell death events in kinase dependent tumors. Polymorphism
also play a critical role in the origination of drug resistance. For example, an intron comprising 2903-bp
deletion in BIM gene recruits privileged splicing of exon 3 over exon 4 produces BIM isoforms which does
not bears BCL-2 homology domain 3 (BH3) domains. This type of BIM protein promotes drug resistance in
NSCLC (non-small cell lung cancer) and CML (chronic myeloid leukemia) against tyrosine kinase inhibitors
such as gefitinib and imatinib .
[67]
Folylpolyglutamate synthase (FPGS) enzyme is involved in the maintenance of folate homeostasis in the
cytosolic and mitochondrial compartment. Exon 12 skipping in FPGS gene results in dysfunctional FPGS
which leads to the inhibition of anti-folate drugs such as methotrexate and introduces resistance in acute
[68]
lymphoblastic leukemia .

CART-19 immunotherapy is well known to recognize the full length CD19 protein which diminishes the
death probability of cancer cells. Skipping of exon 2, in the maturation of CD19 mRNA, results in the
truncated CD19 protein. This splicing event reduces the probability of tumor aggressiveness identification
at the early stage and induces drug resistance . In BRCA1 gene, skipping of exon 11 restores BRCA1 DNA
[69]
[70]
repair potential and stimulates drug resistance .
DNA modification
Epigenetic modifications play a significant role in the expression of various receptor proteins such as
hormone receptors. Tamoxifen treatment downregulates estrogen receptor expression after treatment in
estrogen-responsive breast cancer. This may occur due to epigenetic silencing of the estrogen receptor-
encoding genes. A study has shown that aberrant methylation of CpG islands of the estrogen receptor
promoter and histone deacetylation downregulates its expression and induces tamoxifen resistance.
Overexpression of HER2/EGFR, hypoxia and MAPKs hyper-activation downregulates the estrogen receptor
expression. MiRNA alteration has been directly associated with tamoxifen resistance in breast cancer .
[71]
Steroid receptor coactivator-3 (SRC-3) regulates various processes of cancer development and act as a
coactivator/transcription factor. Breast cancer cells have been reported for the overexpression of SRC-3 and
[72]
positively correlated with tamoxifen resistance . SRC-3 over-expression is also positively correlated with
increased levels of HER-2/neu, poor disease-free survival and tamoxifen resistance in tamoxifen-treated
[73]
breast cancer cells . Epigenetic-driven drug resistance includes epigenetic modification in the gene of
pro-apoptotic (DAPK, APAF-1), drug transporters (ABCB1), histone modifiers (KDM5A) and DNA repair
proteins (MLH1, MGMT, FANCF). Chemotherapeutic drug treatment in drug-resistant cancer cells alters
various enzymes (involved in genome regulation) which makes drug-resistant epigenome to drug-sensitive
epigenome thereby rendering cancer cells sensitive to therapeutic drugs.