Abstract
Papillary renal cell carcinoma (PRCC) is the most common nonclear cell RCCs and is known to comprise two histological subtypes. PRCC2 is more aggressive and is molecularly distinct from the other subtypes. Despite this, PRCCs are treated together as one entity, and they show poor response to the current therapies that do not target pathways implicated in their pathogenesis. We have previously detected ABCC2 (an ABC transporter), VEGF, and mTOR pathways to be enriched in PRCC2. In this study, we assess the therapeutic potential of targeting these pathways in PRCC2. Twenty RCC cell lines from the Cancer Cell Encyclopedia were compared to the Cancer Genome Atlas PRCC cohort (290), to identify representative PRCC2 cell lines. Cell lines were further validated in xenograft models. Selected cell lines were treated in vitro and in vivo (mice models) under five different conditions, untreated, anti‐VEGF (sunitinib), ABCC2 blocker (MK571), mTOR inhibitor (everolimus) and sunitinib + MK571. Sunitinib +ABCC2 blocker group showed a significant response to therapy compared to the other treatment groups both in vitro (P ≤ 0.0001) and in vivo (P = 0.0132). ABCC2 blockage resulted in higher sunitinib uptake, both in vitro (P = 0.0016) and in vivo (P = 0.0031). Everolimus group demonstrated the second best response in vivo. The double‐treatment group showed the highest apoptotic rate and lowest proliferation rate. There is an urgent need for individualized therapies of RCC subtypes that take into account their specific biology. Our results demonstrate that combined targeted therapy with sunitinib and ABCC2 blocker in PRCC2 has therapeutic potential. The results are likewise potentially significant for other ABCC2 high tumors. However, the results are preliminary and clinical trials are needed to confirm these effects in PRCC2 patients.
Highlights
Renal cell carcinomas (RCCs) are tumors that arise from renal tubules
As the ARE pathway is known to be enriched in PRCC2, an ARE PRCC2 gene signature (ABCC2, ACTA2, ACTC1, ACTG2, EPHX1, FTL, GCLM, GPX2, GSR, GSTA1, GSTA2, NQO1, PRKCE, SQSTM1, TXNRD1, AKR1B10, AKR1C1, AKR1C3, SRXN1) (Ooi et al, 2013; the Cancer Genome Atlas (TCGA), 2016) was used to assess the correlation between the PRCC2 and each of the RCC cell lines
The tumors demonstrated diffuse strong staining with ABC binding cassette subfamily C member 2 (ABCC2) (Fig. 1C) as we have previously described in the PRCC2 subtype (Saleeb et al, 2017)
Summary
Renal cell carcinomas (RCCs) are tumors that arise from renal tubules. They represent ~90% of adult kidney tumors and one of the most prevalent malignancies worldwide (Afriansyah et al, 2016; Kumar and Kapoor, 2017). RCCs are, composed of multiple histological types, the most common of which are the clear cell RCCs (CCRCC) (~75%), and the second most common are papillary RCC (PRCC) (10–15%) which is comprised of multiple subtypes (Saleeb et al, 2016). We and others have shown that PRCC subtypes are molecularly and prognostically distinct (Saleeb et al, 2016; TCGA, 2016; Yang et al, 2005). Other RCC subtypes as chromophobe, MiT family translocation RCCs and other rare types collectively constitute the remaining 5–10% (Moch et al, 2016)
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