Abstract：Renal cell carcinoma is one of the most common types of urologic cancer, and its morbidity increases yearly. Nephrectomy is still the standard treatment, however, about 1/3 of the patients were diagnosed with metastastic RCC (mRCC) when first visit. After initial resection, tumor recurrence is observed in 20%-30% cases. As RCC is resistant to traditional chemotherapy, radiotherapy and hormone therapy, strategies in the treatment of mRCC were limited before 2005. The emergence of the targeted drugs has provided more choices for patients with mRCC. However, patients receiving targeted therapy seem to gain limited clinical benefit, and usually are subjected to drug resistance within 6-15 months. This article aims to review the feasible mechanisms of resistance against targeted therapies.
[1]Gupta K, Miller JD, Li JZ, et al. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev, 2008, 34(3): 193-205. [2]Ljungberg B, Campbell SC, Cho HY, et al. The epidemiology of renal cell carcinoma. Eur Urol, 2011, 60(4): 615-621. [3]Huang D, Ding Y, Zhou M, et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res, 2010, 70(3): 1063-1071. [4]Porta C, Paglino C, Imarisio I, et al. Changes in circulating pro-angiogenic cytokines, other than VEGF, before progression to sunitinib therapy in advanced renal cell carcinoma patients. Oncology, 2013, 84(2): 115-122. [5]Kim KJ, Cho CS, Kim WU. Role of placenta growth factor in cancer and inflammation. Exp Mol Med, 2012, 44(1): 10-19. [6]Zhang L, Chen J, Ke Y, et al. Expression of placenta growth factor(PlGF)in non-small cell lung cancer(NSCLC)and the clinical and prognostic significance. World J Surg Oncol, 2005,3:68. [7]Wei SC, Tsao PN, Yu SC, et al. Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut, 2005, 54(5): 666-672. [8]Parr C, Watkins G, Boulton M, et al. Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer, 2005, 41(18): 2819-2827. [9]Chen CN, Hsieh FJ, Cheng YM, et al. The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett, 2004, 213(1): 73-82. [10]Takahashi A, Sasaki H, Kim SJ, et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res, 1994, 54(15): 4233-4237. [11]Matsumoto K, Suzuki K, Koike H, et al. Prognostic significance of plasma placental growth factor levels in renal cell cancer: an association with clinical characteristics and vascular endothelial growth factor levels. Anticancer Res, 2004, 23(6D): 4953-4958. [12]Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell, 2007, 131(3): 463-475. [13]Eriksson A, Cao R, Pawliuk R, et al. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. Cancer Cell, 2002, 1(1): 99-108. [14]Xu L, Cochran DM, Tong RT, et al. Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res, 2006, 66(8): 3971-3977. [15]Hedlund EM, Yang X, Zhang Y, et al. Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs. Proc Natl Acad Sci U S A, 2013, 110(2): 654-659. [16]Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J, 2001, 15(7): 1239-1241. [17]Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer, 2008, 8(8): 592-603. [18]Cao Z, Shang B, Zhang G, et al. Tumor cell-mediated neovascularization and lymphangiogenesis contrive tumor progression and cancer metastasis. Biochim Biophys Acta, 2013, 1836(2): 273-286. [19]Cooke VG, Lebleu VS, Keskin D, et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by Met signaling pathway. Cancer Cell, 2012, 21(1): 66-81. [20]Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 2007, 356(2): 125-134. [21]Gotink KJ, Broxterman HJ, Labots M, et al. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res, 2011, 17(23): 7337-7346. [22]Houk BE, Bello CL, Poland B, et al. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol, 2010, 66(2): 357-371. [23]Khalil B, Hudson J, Williams R, et al. Reprint of: Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: Correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol, 2015, 33(4):171-178. [24]Sierra JR, Cepero V, Giordano S. Molecular mechanisms of acquired resistance to tyrosine kinase therapy. Mol Cancer, 2010,9:75. [25]Azam F, Mehta S, Harris AL. Mechanisms of resistance to antiangiogenesis therapy. Eur J Cancer, 2010, 46(8): 1323-1332. [26]Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell, 2009, 15(3): 220-231. [27]Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer, 2008, 8(6): 425-437. [28]Varna M, Gapihan G, Feugeas JP, et al. Stem cells increase in numbers in perinecrotic areas in human renal cancer. Clin Cancer Res, 2015, 21(4): 916-924. [29]Huang B, Huang YJ, Yao ZJ, et al. Cancer stem cell-like side population cells in clear cell renal cell carcinoma cell line 769P. PLoS One, 2013, 8(7): e68293. [30]Jiang BH, Liu LZ. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist Updat, 2008, 11(3): 63-76. [31]Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci, 2009, 122(Pt 20): 3589-3594. [32]Wang L, Harris TE, Roth RA, et al. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem, 2007, 282(27): 20036-20044. [33]Choo AY, Yoon SO, Kim SG, et al. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci U S A, 2008, 105(45): 17414-17419. [34]Kucejova B, Pea-Llopis S, Yamasaki T, et al. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol Cancer Res, 2011, 9(9): 1255-1265. [35]Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 2005, 307(5712): 1098-1101. [36]Battelli C, Cho DC. mTOR inhibitors in renal cell carcinoma. Therapy, 2011,8(4): 359-367. [37]Thoreen CC, Kang SA, Chang JW, et al. An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1. J Biol Chem, 2009,284(12): 8023-8032. [38]Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest, 2008, 118(9): 3065-3074. [39]Zhao Y, Ehara H, Akao Y, et al. Increased activity and intranuclear expression of phospholipase D2 in human renal cancer. Biochem Biophys Res Commun, 2000, 278(1): 140-143. [40]Shanmugasundaram K, Block K, Nayak BK, et al. PI3K regulation of the SKP-2/p27 axis through mTORC2. Oncogene, 2013, 32(16): 2027-2036. [41]Khaleghpour K, Pyronnet S, Gingras AC, et al. Translational homeostasis: eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities. Mol Cell Biol, 1999, 19(6): 4302-4310. [42]Veilleux A, Houde VP, Bellmann K, et al. Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. Mol Endocrinol, 2010, 24(4): 766-778. [43]Wang K, Li Z, Chen Y, et al. The pharmacokinetics of a novel anti-tumor agent, beta-elemene, in Sprague-Dawley rats. Biopharm Drug Dispos, 2005, 26(7): 301-307. [44]Zhan YH, Liu J, Qu XJ, et al. β-Elemene induces apoptosis in human renal-cell carcinoma 786-0 cells through inhibition of MAPK/ERK and PI3K/Akt/ mTOR signalling pathways. Asian Pac J Cancer Prev, 2012, 13(6): 2739-2744. [45]Martina JA, Chen Y, Gucek M, et al. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy, 2012, 8(6): 903-914. [46]Zheng B, Zhu H, Gu D, et al. MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib. Biochem Biophys Res Commun, 2015, 459(2): 234-239.
