OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy

Abstract

Background:Treatment of advanced and metastatic colorectal cancer with irinotecan is hampered by severe toxicities. The active metabolite of irinotecan, SN-38, is a known substrate of drug-metabolising enzymes, including UGT1A1, as well as OATP and ABC drug transporters.Methods:Blood samples (n=127) and tumour tissue (n=30) were obtained from advanced cancer patients treated with irinotecan-based regimens for pharmacogenetic and drug level analysis and transporter expression. Clinical variables, toxicity, and outcomes data were collected.Results:SLCO1B1 521C was significantly associated with increased SN-38 exposure (P<0.001), which was additive with UGT1A1*28. ABCC5 (rs562) carriers had significantly reduced SN-38 glucuronide and APC metabolite levels. Reduced risk of neutropenia and diarrhoea was associated with ABCC2–24C/T (odds ratio (OR)=0.22, 0.06–0.85) and CES1 (rs2244613; OR=0.29, 0.09–0.89), respectively. Progression-free survival (PFS) was significantly longer in SLCO1B1 388G/G patients and reduced in ABCC2–24T/T and UGT1A1*28 carriers. Notably, higher OATP1B3 tumour expression was associated with reduced PFS.Conclusions:Clarifying the association of host genetic variation in OATP and ABC transporters to SN-38 exposure, toxicity and PFS provides rationale for personalising irinotecan-based chemotherapy. Our findings suggest that OATP polymorphisms and expression in tumour tissue may serve as important new biomarkers.

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology

“…In advanced cancer patients treated with single-agent irinotecan, the SLCO1B1*1b haplotype was associated with a lower absolute neutrophil count nadir when comparing *1b/1b patients to *1a/1a or *1a/1b patients (Innocenti et al, 2009); conversely, the c.388A.G variant was associated with a protective effect against neutropenia following irinotecan therapy in another study (Crona et al, 2016). With regard to outcomes, patients with the c.521T.C variant had increased SN-38 exposure compared with wild type, and those with the SLCO1B1 c.388GG genotype had significantly longer progression-free survival compared with the c.388AA genotype (Teft et al, 2015). Collectively, these genetic association studies demonstrate that SLCO1B1 variation may play an important role in the interindividual variability in chemotherapy disposition and response for several OATP1B1 chemotherapeutic substrates.…”

Endogenous retroviral promoter exaptation in human cancer

“…The novel protein is believed to be intracellular and its role in cancer remains unclear. However, one study showed that high expression of this isoform is correlated with reduced progression-free survival in colon cancer [136]. …”

Impact of Transporter Polymorphisms on Drug Development: Is It Clinically Significant?

“…Unlike c.521T>C, c.388A>G is associated with lower plasma concentrations of various statins, and homozygous variant carriers have shown increased low‐density lipoprotein (LDL) reduction in response to atorvastatin treatment when compared with heterozygous and homozygous wild‐type individuals . Interestingly, Teft et al found that although c.521C was significantly associated with increased exposure to the active metabolite of irinotecan, the progression‐free survival (PFS) was significantly longer in c.388G/G advanced cancer patients treated with irinotecan‐based regimes . Moreover, c.521T>C and c.388A>G can be in linkage disequilibrium and result in 4 functionally distinct haplotypes with varying effects on drug disposition …”

“…18 Interestingly, Teft et al found that although c.521C was significantly associated with increased exposure to the active metabolite of irinotecan, the progression-free survival (PFS) was significantly longer in c.388G/G advanced cancer patients treated with irinotecan-based regimes. 19 Moreover, c.521T>C and c.388A>G can be in linkage disequilibrium and result in 4 functionally distinct haplotypes with varying effects on drug disposition. 8 OATP1B3.…”