Introduction
Lung carcinoma is the second most common type of cancer (accounting for
13% of all occurrences) and the leading cause of carcinoma fatalities
(23% of the total cases).1 It only has a 15% 5-year
survival rate, and the median survival time is even less than tenmonths.
Moreover, regardless of histological type, half of all lung cancer
patients develop metastatic or advanced malignancy (stages III and IV)
at the time of diagnosis. Patients with advanced lung cancer are
administered platinum-based doublet chemotherapy. Even though cisplatin
or carboplatin is effective when coupled with non-platinum-based
chemotherapy medications such as paclitaxel, pemetrexed, irinotecan, or
gemcitabine, significant diversity in treatment response has been
reported.2 Different individuals react to the same
drug in different ways. Although many genetic and environmental factors
such as age, concurrent therapy, drug interactions, and the nature of
the disease can impact chemotherapy outcomes, there are plenty of
inter-individual differences in drug response due to sequence variants
of genes that encode drug transporters.3
Drug transporters are known mediators of drug disposition, facilitating
the influx of substrates into cells and the efflux of drugs and
metabolites from cells.Solute carrier (SLC) transporters are the most
prominent family of the membrane proteins accountable for the uptake
transport of numerous endogenous and xenobiotic compounds.
These transporters are expressed widely in the human body, but notably
in the epithelia of essential organs such as the liver, gut, kidney, and
lung.4 These transporters are also involved in
multiple physiological processes, such as the cellular uptake of
nutrients, xenobiotics, and absorption of chemotherapeutic drugs (Figure
1).5 SLC transporters are expressed in many tumors and
differentially in malignant and non-malignant
tissues.6 Among the SLC transporter family members,
polymorphism in SLC19A1 , SLCO1B1 , and SLCO1B3 are
reported widely in different carcinomas, and outcomes have sparked
curiosity in studying the function of these transporters in cancer
progression.6
SLC19A1 encodes reduced folate carrier protein (RFC) and
facilitates the movement of antifolate drugs used in cancer
chemotherapy. The efficacy of chemotherapeutic drugs is associated with
the activity and levels of SLC transporters in both cancer and normal
tissues.7 The RFC gene is highly polymorphic in nature
and among the various SNP variants in the SLC19A1 gene,
polymorphism G80A (Arg27His, rs1051266) is
usually studied in different clinical conditions. This variant has been
extensively researched for its role in transport uptake and its
correlation to cancer risk, treatment response, and toxicity. G to
A polymorphism results in the substitution of arginine amino acid with
histidine and thus leads to the alteration in the SLC19A1transporter structure, affecting its function8, thus
modifying drug bioavailability and influencing the therapeutic
outcome.Reports in the past have revealed a significant association of
mutant genotype (AA ) of G80A polymorphism
with an elevated risk of esophageal and gastric carcinoma,
respectively.9 Increased influx of the methotrexate
drug has also been reported in patients with mutant genotype (AA )
because G80A mutation may be responsible for
the increased transporter activity.10 Adjei et
al . concluded that SLC19A1 seems to predict survival differences
in pemetrexed-treated NSCLC patients.11
Solute carrier organic anion transporting polypeptides (OATP) is another
SLC drug transporter that mediates the cellular influx of various
chemotherapeutic drugs into the cell. Among these transporters,SLCO1B1 (OATP1B1) and SLCO1B3 (OATP1B3) are theessential
proteins localized at the basolateral membrane of the
hepatocytes.12 Overexpression of SLCO1B1 andSLCO1B3 has been reported in ovarian, prostate, breast, and lung
cancer (Sutherland et al., 2020).6 Various genetic
polymorphisms are described in the SLCO1B1 gene; among them,
themost relevant SNPs related to drug disposition areA388G (rs2306283) andT521C (rs4149056). Reports have suggested some
controversial results with the A388G variant as
some studies have reported that A388G is
significantly correlated with the increased expression ofSLCO1B1 , assuring increased transporter activity, while others
have demonstrated unaltered transporter function.13-15On the other hand, variant T521C has been
correlated with lower expression of OATP1B1 protein and significantly
reduced transport activity compared to the wild type (TT )
genotype.13-16 Another variant of OATP is an intronic
region mutation of SLCO1B3A1683-5676G(rs11045585) associated with the docetaxel-induced
leukopenia.17 SLCO1B3 is a highly polymorphic
gene that displays notable allele frequencies variations among various
ethnic populations. Polymorphism in the SLCO1B3 gene has been
correlated with the altered OATP activity that often leads to
drug-associated adverse events. Yamada et al. reported that the
increased rate of the A1683-5676G variant might
contribute to the reduced SLCO1B3 function that may alter
therapeutic efficacy.18
Our research aimed to determine the role of SLC19A1 ,SLCO1B1 , and SLCO1B3 gene polymorphism in North Indian
lung cancer patients. The findings could help us better understand the
molecular mechanisms underlying altered OATP expression, anticancer drug
transport, cancer development, and therapy efficiency and see if these
transporters can be harnessed as potential diagnostic and predictive
molecular markers. To the best of our knowledge, no such studies
evaluating the role of these polymorphisms in lung cancer have been
undertaken in the North Indian lung cancer patients.