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

Abstract

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.

Resistance to Systemic Therapies in Clear Cell Renal Cell Carcinoma: Mechanisms and Management Strategies

“…Significant molecular heterogeneity was also detected between primary and metastatic lesions, with only a small subset of alterations present in both sites. In one study, post-sunitinib metastatic lesions carried mutations in FLT4, KMT2D, and BMP5, which were not detected in the primary tumor (90). Studies by Hatiboglu et al demonstrated that although neoadjuvant treatment with sorafenib was clinically active in downsizing tumors in patients with locally confined, non-metastatic ccRCC, such treatment led to an enhanced functional ITH in the residual tumor tissue (91).…”

Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study

“…1 Although many treatments are available for patients with advanced RCC, complete and durable tumor responses have not been achieved in the majority of patients, probably because of intratumor heterogeneity and diverse mechanisms of drug resistance leading to tumor growth. [2][3][4][5][6][7][8] Thus, the development of new agents and combination therapies to improve clinical outcome is warranted.…”

Perfil molecular tumoral del cáncer pulmonar medido por secuenciación de nueva generación

“…Dicha prueba evalúa de manera simultánea las mutaciones en diferentes genes, incluyendo el EGFR, reordenamientos en el gen de la ALK, genes B-Raf (BRAF), ROS-1, K-RAS, MET y HER2 y varias otras moléculas que regulan diferentes vías de traducción de señales como son las vías de MAP cinasas o PI3K-AKT-MTOR. 16 Hasta el momento la FDA ha aprobado diversos TKI contra los siguientes blancos terapéuticos: EGFR, BRAF, ROS1 y ALK. 17 Varias mutaciones genéticas se han identificado como posibles blancos terapéuticos.…”