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Kumar et al. Cancer Drug Resist 2019;2:161-77 I http://dx.doi.org/10.20517/cdr.2018.27 Page 169

drug resistance and increased aggressiveness in cancer cells. Transcription factors superfamily comprising
DNA binding domain includes Forkhead box (FOX) proteins. FOX has been reported to regulate cellular
machinery and various homeostatic processes. FOX factors controls numerous physiological processes
including cell division, cell death, cell invasion and migration and drug resistance [98-100] . FOXO3a receives
signals from the signaling pathways such as EGFR/PI3K/Akt/ERK, and transfers it to other pathway which
ultimately controls transcription of respective gene. Sometimes these factors alone bind to the regulatory
region of the promoter and thereby regulate gene transcription. Hyperactivation of PI3K/Akt signaling
inactivates FOX factors and induces drug resistance. Mutation in the PTEN gene and receptor tyrosine
kinases overexpression together endorses cancer development and drug resistance [101] . Several studies
revealed that anticancer drugs such as imatinib, tamoxifen, cisplatin, doxorubicin, paclitaxel, lapatinib and
gefitinib induce FOXO activation via alteration in PI3K/Akt signaling pathways [99,102-105] . JNK signaling also
promotes FOXO3a nuclear localization and activity by diminishing Akt phosphorylation [102,103] [Figure 3].
The p38 protein actively phosphorylates FOXO3a at Serine 7 residue which in turn enhances its nuclear
[98]
re-localization and provides doxorubicin directed response . Another FOX family factor, FOXM1 acts
like an oncogenic transcription factor mainly controls cell cycle and division. FOXM1 is overexpressed in
several cancers including breast, liver, colorectal, lung and the prostate [106] . Oncogenic potential of FOXM1
and its uncontrolled cell division properties makes it available in the stem cell compartments and initiate
hyperplasia. FOXM1 imparts resistance against chemotherapeutic drugs such as epirubicin and cisplatin
[Figure 3]. It also induces drug resistance via overexpression of DDR gene viz. replication factor C4 (RFC4),
epsilon 2, accessory subunit (POLE2), polo-like kinase 4 (PLK4), X-ray repair complementing defective repair
in Chinese hamster cells (XRCC1), breast cancer type 2 susceptibility protein (BRCA2), polymerase (DNA
directed) and exonuclease 1 (EXO1) [107-109] . Furthermore, FOXM1 and FOXO3a together compete for the
same DNA sequences for binding. These factors also share numerous target genes which facilitates FOXM1
transcriptional output repression by FOXO3a proteins. However, FOXO3a prevents VEGF expression and
FOXM1 facilitates VEGF overexpression to regulate cell migration, invasion and drug resistance.

Focal adhesion kinase
Focal adhesion kinase (FAK), a tyrosine kinase also referred as PTK2 (non-receptor protein tyrosine kinase)
is a downstream protein of integrin and growth factor receptors signaling pathways. Increased expression
of FAK has been associated with various type of cancer [110] . FAK modulates tumor progression, apoptosis,
invasion, and metastasis. The N and C terminal domains (FERM and FAT domains) of the protein hinders
the ATP binding site of the central kinase domain. The interaction between N and C terminal domain of the
protein keeps it in an inactive form. Integrin and growth factor receptor activation induce disruption of N and
C terminal domain resulting in the exposed ATP binding site on the central kinase domain. Binding of ATP
to the central domain, phosphorylation of FAK-Y397 amino acid followed by SRC binding, and additional
amino acid phosphorylation results in the activated FAK [111] . FAK induces PIP2/3 and AKT1-mediated
survival signals in cells. FAK induces BCAR1 (breast cancer anti-estrogen resistance 1) and MAPK8 mediated
cellular motility, proliferation, and survival in breast cancer. Beside FAK induces assembly and disassembly
(turnover) of the focal adhesions and thus modulate migration of cells [112] . FAK is known to interact with
some other proteins such as GRB2, TP53, MDM2, and RIP associated with the pathogenesis of cancer [113] .
From the above discussion, it is clear that ATP binding domain and some other FAK domains involved in
protein-protein interaction might serve as a cancer drug target. Inhibitors (VS-4718; VS-6062 and PF-573,228)
[113]
having the binding ability to these domains serve as a promising candidate in anticancer drug discovery .
Studies indicate the promising efficacy of FAK inhibitors and chemotherapy synergism to reduce treatment
side effects and drug resistance in cancer. These inhibitors increase chemosensitivity in drug-resistant cells
[113]
and also synergize the drug treatment efficacy in cancer cells . Recent reports suggest that FAK induces NF-
κB pathway mediated cytokine production in response to DNA damage. This phenomenon protects the cells
[114]
from DNA damage and maintains chemo-resistance in the cells . In this regard, FAK inhibitors might play
a critical role against DNA damage-mediated drug resistance in cancer cells.