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.