J Cancer 2019; 10(14):3224-3231. doi:10.7150/jca.30130 This issue

Research Paper

Tumoral Pyruvate Kinase L/R as a Predictive Marker for the Treatment of Renal Cancer Patients with Sunitinib and Sorafenib

Marjut Niinivirta1,2, Gunilla Enblad1,2, Cecilia Lindskog3, Fredrik Pontén3, Anca Dragomir3,4, Gustav J. Ullenhag1,2✉

1. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2. Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden
3. Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85 Uppsala, Sweden.
4. Department of Surgical Pathology, Uppsala University Hospital, 75185 Uppsala, Sweden.

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Niinivirta M, Enblad G, Lindskog C, Pontén F, Dragomir A, Ullenhag GJ. Tumoral Pyruvate Kinase L/R as a Predictive Marker for the Treatment of Renal Cancer Patients with Sunitinib and Sorafenib. J Cancer 2019; 10(14):3224-3231. doi:10.7150/jca.30130. Available from https://www.jcancer.org/v10p3224.htm

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Background and aims: Treatment with tyrosine kinase inhibitors (TKI) like sunitinib and sorafenib has improved the prognosis of patients with metastatic renal cell cancer (mRCC). No predictive marker is available to select patients who will gain from these treatments. Tumoral pyruvate kinase L/R (PKLR) is a membrane protein with highly specific expression in the renal tubule. We have previously shown that the tumoral expression of cubilin (CUBN) is associated with progression free survival (PFS) in mRCC patients treated with sunitinib and sorafenib. The aim of the present study was to investigate if PKLR can predict response in these patients, alone and/or in combination with CUBN.

Methods: A tissue microarray (TMA) was constructed of tumor samples from 139 mRCC patients. One hundred and thirty-six of these patients had been treated with sunitinib or sorafenib in the first or second-line setting. Thirty patients suffered from early severe toxicity leading to the termination of treatment. The remaining patients (n=106) were selected for the current study.

Results: Fifty-five (52%) of the tumors expressed membranous PKLR. Patients with PKLR tumor expression experienced a significantly longer PFS compared to patients with no expression (eight versus five months, p = 0.019). Overall survival (OS) was also significantly better for patients with PKLR expression. In addition, the combined expression of PKLR and CUBN resulted in a higher predictive value than either marker alone.

Conclusions: In this real world study we show that tumoral PKLR membrane expression is a positive predictive biomarker for sunitinib and sorafenib treatment in patients suffering from mRCC. Our results also indicate that the combined expression with cubilin more accurately than PKLR alone can select patients with no benefit from treatment.

Keywords: PKLR, predictive marker, renal cancer, tyrosine kinase inhibitor