Open AccessModulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy
Author(s) -
Saleeb Rola M.,
Farag Mina,
Lichner Zsuzsanna,
Brimo Fadi,
Bartlett Jenni,
Bjarnason Georg,
Finelli Antonio,
Rontondo Fabio,
Downes Michelle R.,
Yousef George M.
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12346
Subject(s) - sunitinib , everolimus , papillary renal cell carcinomas , in vivo , cancer research , pi3k/akt/mtor pathway , renal cell carcinoma , medicine , targeted therapy , pharmacology , cancer , biology , signal transduction , microbiology and biotechnology
Papillary renal cell carcinoma ( PRCC ) is the most common nonclear cell RCC s and is known to comprise two histological subtypes. PRCC 2 is more aggressive and is molecularly distinct from the other subtypes. Despite this, PRCC s 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 ABCC 2 (an ABC transporter), VEGF , and mTOR pathways to be enriched in PRCC 2. In this study, we assess the therapeutic potential of targeting these pathways in PRCC 2. Twenty RCC cell lines from the Cancer Cell Encyclopedia were compared to the Cancer Genome Atlas PRCC cohort (290), to identify representative PRCC 2 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), ABCC 2 blocker ( MK 571), mTOR inhibitor (everolimus) and sunitinib + MK 571. Sunitinib + ABCC 2 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). ABCC 2 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 ABCC 2 blocker in PRCC 2 has therapeutic potential. The results are likewise potentially significant for other ABCC 2 high tumors. However, the results are preliminary and clinical trials are needed to confirm these effects in PRCC 2 patients.