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Drug resistance in papillary RCC: from putative mechanisms to clinical practicalities

Nature Reviews Urology volume 16, pages 655–673 (2019)Cite this article

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Abstract

Papillary renal cell carcinoma (pRCC) is the second most common renal cell carcinoma (RCC) subtype and accounts for 10–15% of all RCCs. Despite clinical need, few pharmacogenomics studies in pRCC have been performed. Moreover, current research fails to adequately include pRCC laboratory models, such as the ACHN or Caki-2 pRCC cell lines. The molecular mechanisms involved in pRCC development and drug resistance are more diverse than in clear-cell RCC, in which inactivation of VHL occurs in the majority of tumours. Drug resistance to multiple therapies in pRCC occurs via genetic alteration (such as mutations resulting in abnormal receptor tyrosine kinase activation or RALBP1 inhibition), dysregulation of signalling pathways (such as GSK3β–EIF4EBP1, PI3K–AKT and the MAPK or interleukin signalling pathways), deregulation of cellular processes (such as resistance to apoptosis or epithelial-to-mesenchymal transition) and interactions between the cell and its environment (for example, through activation of matrix metalloproteinases). Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies. Further studies on novel resistance biomarkers are needed to improve patient prognosis and stratification as well as drug development.

Key points

  • Papillary renal cell carcinoma (pRCC) can be classified into two subtypes on the basis of genetic background: type 1 pRCC is characterized by MET alterations and type 2 pRCC has alterations in CDKN2A, SETD2, BAP1, PBRM1, FH, NF2, TFE3, NFE2L2 and ARE.

  • Current pRCC treatment options include tyrosine kinase inhibitors (TKIs), such as sunitinib, sorafenib and axitinib, and the mammalian target of rapamycin (mTOR) inhibitor everolimus; however, response rates and survival are low, and most patients develop acquired drug resistance.

  • Drug resistance has been modelled in vivo and in vitro in the two most commonly used pRCC cell lines, ACHN and Caki-2, and these cells are frequently used to investigate resistance mechanisms. However, new tools such as organoids and patient-derived xenografts are promising for studying resistance mechanisms.

  • Resistance to TKIs is mediated by aberrant phosphorylation of tyrosine kinases, dysregulation of PI3K–AKT–MAPK signalling pathway, hypoxia, microRNAs, deregulation of apoptosis and cancer stem cells, among others.

  • Dysregulation of the mTOR, GSK3β–EIF4EBP1 and PI3K–AKT–MAPK signalling pathways, deregulation of apoptosis, and promotion of epithelial-to-mesenchymal transition are the key mechanisms of resistance to mTOR inhibitors.

  • Several therapeutic options for overcoming drug resistance in pRCC are being investigated in vitro, in vivo and in clinical trials, but none of them have been applied in clinical practice.

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Fig. 1: Mechanisms of intrinsic and acquired resistance to TKIs.
Fig. 2: Molecular mechanisms of resistance to TKIs in pRCCs.
Fig. 3: Pathways involved in pRCC resistance.
Fig. 4: Changes in proapoptotic and antiapoptotic factors associated with resistance to TKIs, mTORis and chemotherapy.
Fig. 5: Mechanisms of intrinsic and acquired resistance to mTORis.
Fig. 6: Mechanisms of action of targeted therapies in pRCCs and possible drug-resistance-development mechanisms at a cellular level.
Fig. 7: Potential applications of TKI resistance markers in clinical practice.

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Acknowledgements

This work was supported by the National Science Centre (NCN, Poland) OPUS grant no. UMO-2014/13/B/NZ1/04010.

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Author notes

  1. Anna Brodziak & Paweł Sobczuk

    Present address: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

  2. Cezary Szczylik

    Present address: Department of Oncology, European Health Centre, Otwock, Poland

  3. Cezary Szczylik

    Present address: Medical Centre for Postgraduate Education, Warsaw, Poland

  4. These authors contributed equally: Anna Brodziak, Paweł Sobczuk.

Authors and Affiliations

  1. Department of Oncology, Military Institute of Medicine, Warsaw, Poland

    Anna Brodziak, Paweł Sobczuk, Cezary Szczylik & Anna M. Czarnecka

  2. Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland

    Anna Brodziak & Paweł Sobczuk

  3. Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland

    Ewa Bartnik

  4. Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland

    Ewa Bartnik

  5. Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

    Michał Fiedorowicz

  6. Division of Translational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, Pavia, Italy

    Camillo Porta

  7. Department of Internal Medicine, University of Pavia, Pavia, Italy

    Camillo Porta

  8. School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland

    Cezary Szczylik

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All authors made substantial contributions to discussions of content and edited and reviewed the manuscript before submission. A.M.C., A.B., P.S. and M.F. researched data and wrote the article.

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Brodziak, A., Sobczuk, P., Bartnik, E. et al. Drug resistance in papillary RCC: from putative mechanisms to clinical practicalities. Nat Rev Urol 16, 655–673 (2019). https://doi.org/10.1038/s41585-019-0233-z

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