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Global Translational Medicine Role of HTS in cancer therapeutics

poses a challenge in achieving effective cancer therapy and expression of Pik3ca(H1047R), which accelerated more
and underlines the need for innovative approaches to aggressive tumor development. Furthermore, they determined
overcome or bypass drug resistance mechanisms. 124-127 A its role in cancer cell fate switches depending on its expression
study on mdr1a mice has reported that P-glycoprotein in basal and luminal cells. Since PI3K signaling is involved
-/-
(P-gp) hampers the oral uptake of paclitaxel. There in multiple cellular processes, including cell survival and
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were several efforts made to generate inhibitors to cell death mechanisms, Li et al. developed and implemented
reverse chemoresistance caused by overexpression of a high-throughput paired cell-based screen composed
high-molecular-weight surface P-gp. 129,130 In clinical of parental HCT116 cells and their PTEN gene-targeted
trials, third‑generation modulators such as LY335979, derivatives to identify small molecules that preferentially kill
R101933, and XR9576 have shown better accumulation cells with mutations of PTEN. Among 138,758 compounds
of P-gp substrate Tc-99m sestamibi, an imaging agent, tested, two hits were identified and finally, N’-[(1-benzyl-
in a subset of patients. 131-133 However, these inhibitors 1H-indol-3-yl)methylene]benzenesulfonohydrazide
did not perform well in the clinical trials due to low (CID1340132) was determined as a novel compound that
bioavailability, unexpected secondary physiological induces apoptosis preferentially in PTEN and PIK3CA mutant
effects, and unanticipated drug-drug interactions. 125,134 human cancer cells. 151
Therefore, several assays have been designed using
human MDR cell lines to aid in the discovery of novel The stemness of nasopharyngeal carcinoma (NPC)
inhibitors against efflux pump P-gp coded by the MDR1/ cells is not only controlled by PI3K signaling but also
ABCB1 gene and other ABC transporters. Efforts have by Wnt signaling that promotes migration and invasion
been made to prepare drug-sensitive and -resistant of cancer cells by upregulating expression of WNT5A
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human myeloma cell lines, 8226/S, and 8226/Dox6 to in biopsy samples of metastatic NPC tissues. To study
demonstrate association of P-gp overexpression with Wnt signaling role in cancer treatment, specifically the
resistance to glucocorticoid, etoposide, doxorubicin, and inhibition of intracellular β-catenin turnover and the
vincristine. Collectively, studies have identified several formation of a nuclear β‑catenin/T cell factor (TCF)
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compounds, such as mometasone furoate, NSC23925, transcription complex, TCF/lymphoid enhancer factor
NSC77037, pimozide, acacetin, and loxapine, as a tolerable family (TCF/LEF) luciferase reporter assay is highly used
and effective therapy to reverse MDR. 136-139 Therefore, key because Wnt/β-catenin works through either activating or
components such as P‑gp, ABC transporters, and MDR repressing transcription of genes whose promoters contain
could be potential candidates of chemoresistance, which binding sites for TCF‑transcription factors. To search for
can be targeted in cancer drug discovery. specific inhibitors against the formation of this complex,
Wan et al. prepared cell lines to perform cell-based assay to
Another challenge to cancer treatment is the stemness screen a diverse library of small molecules. They developed
caused by cancer stem cell (CSC) that can differentiate cell lines with constitutive Wnt signaling, 153,154 using an
into other cell types of cells in the body due to phenotypic inducible HEK cell line, which expresses Dvl2 fusion
plasticity following transcriptional reprogramming driven consisting of estrogen receptor (ER), luciferase, and GFP
by an evolutionarily conserved starvation response causing genes, under the control of a minimal c-Fos promoter with
cancer progression and recurrence. This leads to high TCF‑binding sites and Xnr3 enhancer. This cell line helps
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heterogeneity among tumor tissue environments causing in screening β‑catenin inhibitors such as CCT031374,
drug resistance. Transcriptional reprogramming helps CCT036477, and CCT7070535 that block β-catenin
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cancer cells not only to escape from the host immune induction on estradiol addition. These compounds were
defense system but also to stimulate invasion, proliferation, able to not only block the induction of β-catenin activity
and metastasis. 142,143 This heterogeneity in the tumor but also reduce the proliferation of colorectal cancer cell
microenvironment creates complexity in the signaling lines (HCT116, HT29, and SW480) and induce caspase 3
pathways due to unstable and altered genetic and epigenetic activation in HCT116 cells.
profiles that make drug discovery processes more difficult. 144,145
Genetical modifications and several key pathways such as Exploring the disruption of TCF signaling, specifically
Wnt, phosphoinositide 3-kinase signaling pathway (PI3K) TCF4 and β-catenin, to search for anticancer drugs, has
signaling, interferons (IFNs), and Erk/MAPK signaling are been attempted by Lepourcelet et al., who screened
involved in this reprogramming. 146-149 A detailed study by Van libraries of natural compounds in an HTS manner for
Keymeulen et al. has demonstrated how tumor heterogeneity immunoenzymatic detection of the protein-protein
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is determined by the cancer cell origin using Cre‑inducible interaction. Finally, they were able to select two fungal
Pik3ca H1047]R knock‑in mice, specifically in basal cells (BCs) derivatives (PKF115‑854 and CGP049090) that passed
using K5‑CreER mice. The mice exhibited deletion of p53 the tested predictions including disruption of Tcf/β-
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Volume 3 Issue 1 (2024) 10 https://doi.org/10.36922/gtm.2448