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The availability of tyrosine kinase inhibitors (TKI) during the past ten years has led to improved response and overall survival of patients suffering from metastatic clear cell renal cell carcinoma (ccRCC). However, most of these tumors will eventually progress due to resistance evolving under therapy. The objective of this pilot study was to determine whether molecular alterations in ccRCC tissues sampled over the course of the disease might be suggestive of potential therapies. We performed whole exome sequencing of nine samples from four patients in the MORE (Molecular Renal Cancer Evolution) trial. We analyzed the mutational patterns in the tissues at baseline and compared them to those detectable in biopsy samples after progression under TKI therapy. We found limited genetic concordance between primary and secondary tumor sites with private mutations in FLT4, MTOR, ITGA5, SETD2, PBRM1 , and BRCA1 on progression. One patient who showed an increased mutational load in the metastasis responded to nivolumab treatment. Our data provide evidence for clonal evolution and diverse pathways leading to acquired TKI resistance of ccRCC. Acquired resistance to TKI in metastatic ccRCC is due to intra-tumor heterogeneity and clonal evolution of resistant subclones. Mutations occurring under progression might be informative for alternative targeted therapies.

Patient-specific molecular alterations are associated with metastatic clear cell renal cell cancer progressing under tyrosine kinase inhibitor therapy