Literature the main focuses in cancer research is acquired

Review Cancer is a major public health problem
and continues to be one of the leading causes of death (Heron). Cancer-related
illnesses are complex and are a result of the malfunctioning of genes that are
responsible for regulating cell growth division and death (Sudhakar). This
gives rise to uncontrolled growth and proliferation of cancer cells in the
body. Cancer is a multidisciplinary focus medical research as scientists
continue to monitor cancer and further develop effective prevention strategies
(Hermann). One of the main focuses in cancer research is acquired resistance,
as it is a major impediment in tackling cancer. Acquired resistance is a result
of mutations in cancer cells that develop resistance, after initial therapy to
anti-cancer treatments (Zahreddine). Although acquired resistance is a major
hurdle in treating and defeating cancer, there are other factors that also
serve as obstacles in overcoming cancer such as intrinsic resistance,
multi-drug resistance, and the various molecular mechanisms that can cause
resistance.  In order to overcome the
inexorable rise of resistance, researchers have conducted studies to further
investigate the potential use of combination therapies and personalized
medicine.  Cancer is a result of growth of abnormal
cells in the body, and the abhorrent number of cells are capable of invading
surrounding tissues (Pubmed link). Behind cardiovascular diseases, cancer is
the second leading cause of death, and continues to affect people worldwide (Siegl).
Cancer cells continuously grow and proliferate uncontrollably by mitosis, and these
dysregulated cells eventually accumulate and develop into heterogenetic tumours
(Sudhakar). If cancer cells break away from the primary tumour, they can spread
throughout the body and this can result in metastasis (Cooper). The development
of cancer can arise from any type of cell in the body giving rise to a diverse
number of cancers, and their responses towards treatments can differ. Tumours
may also be composed of a heterogenous population of cells amassing genetic and
epigenetic changes that contribute to resistance (Zahreddine).  Chemotherapy and traditional cytotoxic
drugs constitute the backbone in most treatment regiments against cancer.
However, their success and effectiveness against cancer are limited due to the
inexorable rise of drug resistance (Holohan). Scientists had to explore the
diverse molecular mechanisms that underlie cancer growth, and this led to the
development of molecularly targeted therapies due to the disease
specific-mechanisms that are absent in normal cells (Zahreddine). Many of these treatments are used in the
clinic, and patients demonstrated responses to targeted anti-cancer therapies.
Nevertheless, cancer cells cease to react to treatment, and the development of
drug resistance continues to be a major problem (Zahreddine). There are two
types of drug resistance that can emerge: acquired resistance and intrinsic/primary
resistance. Both acquired and intrinsic resistance can arise due to various mechanisms
involving alterations to drug metabolism or drug target modifications
(Zahreddine). Studying drug metabolism, the most studied mode of resistance, involves
analysing the uptake, efflux, and detoxification (Zahreddine). Anti-cancer
drugs will enter a cell based on its chemical nature, usually they target
receptors and transporters to transmit their effects or gain cellular entry,
respectively (Gottesman). Reductions of available transporters or mutations
that modify transporters (Zahreddine). Other modes of resistance can include:
drug inactivation, oncogene addiction, amplification of alternative oncogenes,
and or inactivation of alternative survival pathways (Zahreddine). Once
resistance becomes present in cancer, treating it becomes problematic (Freidman).
 Resistance is not limited issue against
one drug, it can occur in a multitude of treatments and give rise to multi-drug
resistance (Ullah). To overcome cross resistance, combined synthetic lethality
studies have studied interactions between EGFR (epidermal growth factor
receptor) and PARP inhibition in human triple negative breast cancer cells (TNBC)
using a combination of lapatinib and PARP inhibitor ABT-888 (Nowsheen). Triple
negative breast cancer is aggressive type of breast cancer, and it has been
found to be resistant to standard anti-cancer therapeutics such as angiogenesis
inhibitors, EGFR targeted treatments, src kinase, and mTOR inhibitors
(Nowsheen, Chacon). Lapatinib would induce a transient DNA repair deficit,
increasing cytotoxicity to PARP inhibitor ABT-888. The drug reduced the
presence of nuclear BRCA1 and EGFR, induced subcellular localization, and
diminished HR-mediated DNA repair (Nowsheen). The results from the study have
shown that Lapatinib combined with ABT-888 induced the intrinsic pathway of
apoptosis and weakened the survival fraction of TNBC cells.  Patients can have an initial response to
anti-cancer treatments, but with acquired resistance, they can stop responding
to prolonged treatments and thus be responsible for cancer relapse (Housman). Mutations
in a population of cells can arise in acquired resistance because they carry a
selection benefit, the treatment given to a patient will eradicate the
sensitive clones, but select the resistant ones. (Freidman). It has been
proposed that a more aggressive treatment would reduce the likelihood of
mutations emerging (Housman). However, initial treatment will reduce the overall
tumour size, but the remaining population of cells can mutate and even acquire de novo resistance as a result of the
anti-cancer treatment (Frediman). However, patients are always at risk for
developing resistance throughout any point of treatment (Zahreddine).  Experimental evidence has demonstrated
how anti-cancer treatments can give rise to acquired resistance. MDM2
inhibitors, such as nutlin-3, have been shown to give rise to p53-mutated
multi-drug resistant cancer cells, and it is also a non-genotoxic p53 activator
(Michaelis). p53 is a tumour suppressor protein, and is responsible for DNA
repair, and inhibition of the cell cycle, it can also induce apoptosis in
response to genotoxic stress (Michealis). TP53 gene encodes for p53, and has
been found to be the most frequently mutated gene in cancer (Michaelis). It was
previously thought that Nutlin-3 would decrease genomic instability, reduce formation
of resistance cells, and avoid targeting the DNA integrity. It has also been
known that Nutlin-3 to activate p53 responses, as it blocks the interaction
between p53 and its inhibitor MDM2 (Brown). In this study, nutlin-3 induced
resistance formation was observed in a panel of neuroblastoma, rhabdomyosarcoma,
and melanoma cells. The cell panel was chosen for this study as these cancer
cells have been known to have low frequencies of p53 mutations, and nutlin-3 had
also displayed anti-cancer effects against these cancer cells (Michaelis). Only
2 out of 28 melanoma, neuroblastoma, and rhabdomyosarcoma cells lines adapted
to a range of cytotoxic anti-cancer drugs displayed p53 mutations (Michaelis).
This demonstrates that the induction of p53 mutations is an exclusive property
of nutlin-3. However, in experiments using single p53-wild type cell derived
UKF-NB-3 clones it was shown that nutlin-3 induces de novo p53 mutations, and the drug does not select pre-existent p53-mutations
in sub-populations that were already present in the original cell lines
(Michaelis). The results in the study have demonstrated that nutlin-3 treatment
reproducibly displayed an irreversible rise of p53, multi-drug resistant
emergence may not be a suitable cancer treatment option. Patients treated with
MDM2 inhibitor such as Nutlin-3 should be monitored for the rise of p53
mutations in multi-drug resistant cells (Michaelis).  Intrinsic resistance is pre-existent and
the occurrence is present prior to receiving treatment, meaning resistance
mutations can be present in a small subpopulation of tumour cells before the
initiation of therapy (Foo). This is usually a result of the acquisition of
stochastic mutations (Zahreddine). The emerging resistance mutations would be
fixed within the population of tumour cells, after the initiation of treatment
the sub-population of cells carrying the mutation would increase and survive
the insult of therapy (Friedman). With intrinsic resistance, malignant cells
exposed to aggressive treatments will have an increased likelihood of their
pre-existing mutations dictating the tumour cell population. Patients would
then fail to respond with initial treatment (Housman).   Combination therapies are currently
being investigated in clinical research, as a mechanism to overcome resistance
to molecularly targeted therapies. Current studies have demonstrated that the
addition of CDK4/6 inhibitors in combination with existing therapies can
potentially improve patient response and overcome treatment resistance (Hamilton).
The cell cycle is highly regulated by cyclin-dependent kinases (CDKs), but
dysregulation of CDK activity had been detected in a broad range of
malignancies (Hamilton). Aberrant CDK activity can result in continuous growth
and abnormal cell cycle proliferation, and underlying causes can include:
gene amplification or rearrangement, loss of negative regulators, epigenetic
alterations, and point mutations in key pathway components (Hamilton). Existing treatments
that are being investigated for potential combination therapy with CDK4/6 inhibitors
include: hormonal therapy, PI3K/AKT/mTORpathway inhibitors, RAS/RAF/MEK/ERK
pathway inhibotrs, chemotherapy, and radiotherapy (Hamilton). Preclinical
studies have shown promising results in combination therapies. Abemaciclib
had a synerginistic effect on chemotherapy agent gemicitabine (Gelbert), and
palbociclib diminished cytotoxic effects of antimitotics and platinum agents (Gogolin).
Inhibitors of cyclin-dependent kinases (CDKs) 4/6 have shown efficacy and
clinical activity in several malignancies (Knudsen). Targeting the cell cycle with
a powerful class of novel agents will strike a key characteristic in cancer
(Knudsen).  Due to the rise of resistance limiting
the effectiveness of chemotherapy and cytotoxic drugs, researchers are
investigating personalised medicine in treating cancer. Using the systemic use
of genetic information can be beneficial in order understand the molecular
basis of cancer (Garraway, Mukesh Verma). Personalised medicine involves utilizing
this information based on a patient’s individual genetic makeup, and it will
provide a genetic understanding of their disease, in order to tailor therapeutic
care to that patient’s needs (Mukesh Verma). This has been demonstrated with a
non-invasive analysis of circulating tumour DNA (ctDNA). As previously mentioned,
patients with advanced cancer undergo prolonged systemic treatments are likely
to acquire resistant due to clonal evolution (Murtaza). Routinely, serial
tumour biopsies are conducted to further analyse the genomic modification
caused by the treatment, are usually invasive and can be misperceived by tumour
heterogeneity (Murtaza). Previous studies have demonstrated that ctDNA is more
accessible, easier to process, and contains representation of the entire tumour
genome (Murtaza) The ctDNA would also contain mixed variants that had originated
from a variety of independent tumours (Murtaza). In this preliminary study, six
patients that had the following advanced malignancies: breast cancer, ovarian
cancer, or lung cancers were followed over 1-2 years. Exome sequencing on a
variety of samples with each case, and showed proof of genomic evolution and
displayed genome-wide similarities between tumour DNA and ctDNA (Murtaza). The
mutations discovered were found to either be well-recognized oncogenic genes
that have been associated with drug resistance and drug metabolism, or they
were newly discovered genes that had not been known to be linked to drug
resistance or carcinogenesis (Murtaza). One of the patients in the study, with
advanced ovarian cancer was treated with cisplatin. After the treatment, she
had an abundance of mutations in the tumour-suppressor RB1 gene, which is known
for inactivating the RB1 protein (Murtaza). Her matched metastasis biopsy revealed
the mutation was found in 95% of sequencing reads, with a loss of
heterozygosity at 13q containing the RB1 gene (Murtaza). Loss of this gene had
also been associated with chemotherapy response (Murtaza). Other studies have
used this non-invasive technique to analyse ctDNA in EGFR-TKI mutations, and various
Lung Cancers (Zhang, Fiala).