*6.3. Significance of ABCG2 Mutations/Polymorphisms in Cancer Therapy*

Numerous in vitro studies have demonstrated altered efflux of chemotherapeutic agents and reduced drug resistance in cancer cells expressing ABCG2 carrying various SNPs. While an unambiguous role for Q141K has been established, the results on the effect of the V12M variant were conflicting [100,115,133,172]. It is important to note that the specific activity of both V12M and Q141K, i.e., transport activity normalized by the expression level, remained unaltered [100], confirming that these SNPs do not affect the actual transport function. ABCG2-Q141K has been shown to diminish drug efflux and/or to increase sensitivity to various anti-cancer drugs, including methotrexate, numerous TKIs (gefitinib, erlotinib, lapatinib, imatinib, dasatinib, nilotinib), and the topoisomerase I inhibitor indolocarbazole [100,114,115,133,172,173]. In addition to genetic alterations, epigenetic modifications could also modulate drug responses. It has been demonstrated that promoter hypermethylation, which frequently occurs in tumor cells, leads to repressed transcription of the *ABCG2* gene, lowered protein level, and consequently increased drug sensitivity [174].

An increasing number of clinical studies reported that ABCG2 polymorphisms modulate the pharmakinetics of chemotherapeutic drugs and increase the risk of drug-related adverse reactions. Studies rarely report altered drug response or clinical outcomes, but toxic side effects due to elevated drug concentrations or longer exposures. Higher accumulation of the small molecule TKI gefitinib was observed in patients heterozygous for the Q141K variant [81]. In accordance with this finding, higher incidence of gefitinib-induced diarrhea was found in Q141K heterozygotes [175], although another study found no association between susceptibility to gefitinib-induced ADR and the Q141K (or Q126X) polymorphism [176]. No difference was found in the therapeutic outcomes (response and survival) in diffuse large B-cell lymphoma patients carrying Q141K or V12M polymorphism, when treated with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) regimen, but chemotherapy-induced diarrhea was associated with the Q141K genotype [177]. Similarly, a higher incidence of sunitinib-induced severe thrombocytopenia was observed in renal cell carcinoma (RCC) patients carrying the Q141K allele [178]. A case report also documented that an RCC patient homologous for Q141K suffered from toxic side effects of sunitinib treatment, such as severe thrombocytopenia, transaminase elevation, severe hypoxia due to pleural effusion and pulmonary edema, in parallel with efficacious treatment of the tumor [179]. Although the expression of ABCG2-Q141K in

cancer cells resulted in elevated sensitivity to imatinib [114,173], the in vivo effect of Q141K on imatinib accumulation/response is controversial [180–185].

Similarly, the results on the role of this SNP in the pharmacokinetics of camptothecin analogs, such as diflomotecan, 9-aminocamptothecin, topotecan, and irinotecan, are conflicting [186–192]. An interesting dual role for the Q141K polymorphism was found in prostate cancer patients. On one hand, this ABCG2 variant results in elevated cellular retention of folate, which is a rate limiting factor for prostate cancer cell proliferation, thus leading to higher risk for tumor reoccurrence after prostatectomy in patients, who received no drug treatment. On the other hand, docetaxel-treated prostate cancer patients carrying Q141K SNP have a longer survival time because of the reduced drug efflux [193].

Besides Q141K, some other frequent polymorphisms, such as V12M and Q126X, have been included in a limited number of clinical studies investigating the effect of ABCG2 SNPs on cancer chemotherapy and therapy-related toxicity. V12M did not influence clinical outcomes and has no association with ADR; on the contrary, Q126X promoted toxic side effects of gefitinib [176,177,192]. Only sparse information is available on ABCG2 minor variants in connection with tumor drug therapy. The SNPs in the promoter region (-15622C/T) and in intron 1 (1143C/T) conferring reduced ABCG2 levels (Class 5 mutations) elevated pharmacokinetic parameters (AUC and Cmax) of erlotinib [194], and increased the incidence of gefitinib-induced diarrhea in non-small-cell lung cancer patients without affecting the clinical outcomes [195]. An SNP in intron 11 (G>A, rs4148157, MAF = 0.096) also altered the pharmacokinetics (absorption rate constant and maximum concentration) of orally administered topotecan in infants and very young children with brain tumors [196].

As mentioned earlier, ABCG2-inhibiting drugs can also modulate the distribution and toxicity of medications, underscoring the importance of ABCG2 in drug–drug or drug–food interactions. On the other hand, mutations and polymorphisms may potentially alter the potency and/or efficacy of these inhibitors, further complicating the evaluation of drug interactions. Nevertheless, this aspect of ABCG2 polymorphic variants remains to be determined.
