UNC-51-like kinase 1 expression in radical nephrectomy specimens as a predicting factor of progression-free survival in patients with metastatic renal cell carcinoma treated with mammalian target of rapamycin inhibitors

Background: To analyze basal expression levels of multiple components in the autophagy pathway in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (mRCC) treated with mammalian target of rapamycin (mTOR) inhibitors, to identify factors predicting susceptibility to these agents.

Methods: This study included 48 consecutive patients undergoing radical nephrectomy, who were diagnosed with mRCC and subsequently treated with either everolimus or temsirolimus. Expression levels of 5 major molecular markers involved in the signaling pathway associated with autophagy, including autophagy-related protein (Atg)5, Atg9, Beclin1, microtubule-associated protein light chain 3, and UNC-51-like kinase 1 (ULK1), were measured by immunohistochemical staining of primary renal cell carcinoma specimens.

Results: During the observation period of this study (median = 16.2 mo), 36 patients developed disease progression, with a median progression-free survival (PFS) period of 7.6 months. Of several factors examined, bone metastasis, liver metastasis, and ULK1 expression were shown to have significant effects on the response to mTOR inhibitors. PFS was significantly correlated with the expression level of ULK1 in addition to bone and liver metastases on univariate analysis. Of these significant factors, ULK1 expression and liver metastasis were independently associated with PFS on multivariate analysis.

Conclusions: It may be useful to consider expression levels of potential molecular markers in the autophagy pathway, particularly ULK1, in addition to conventional parameters, when selecting patients with mRCC who are likely to benefit from treatment with mTOR inhibitors.