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Page 166 Kumar et al. Cancer Drug Resist 2019;2:161-77 I http://dx.doi.org/10.20517/cdr.2018.27

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

DNA repair
Mutation in gene encoding enzymes involved in DNA damage response (DDR) such as ataxia telangiectasia
[56]
(ATM), ATR, RAD50, and WRN can enhance the risk of cancer emergence and resistance . Single
[57]
nucleotide polymorphisms in DNA repair-associated genes can also induce cancer drug resistance . Some
of the chemotherapeutic drugs such as 5-fluorouracil, epirubicin, cisplatin, and doxorubicin have been well
studied in cancer for their potential to cause damage in the DNA molecule. DNA damage triggers DDR
[58]
proteins to repair the DNA and induces drug resistance in cancer cells . DNA repair associated (DRCA)
genes directly regulate DNA repair pathway via the homologous recombination and DNA strand breaks.
Development of inhibitors for these proteins are directly involved in the repair pathway can reduce drug
resistance and sensitize to these agents. Poly ADP-ribose polymerase 1 (PARP1) is an important protein
which modified nuclear proteins through the poly ADP-ribosylation and makes them active for the DNA
damage repair. Olaparib, USFDA approved drug, is a PARP inhibitor which blocks DNA repair functions
[58]
and induces apoptosis in cancer cells . Another DNA repair gene namely NEK2, codes serine/threonine
mitotic kinase plays an important role in spindle formation and chromosome segregation [59,60] . Silencing
of NEK2 reduces drug resistance to bortezomib in vitro and in vivo. NER pathway comprises excision