Scientific publication in Medical Biology – Mechanisms of resistance to targeted therapies

The majority of clear cell Renal Cell Carcinoma (ccRCC) patients carry genetic aberrations of the von Hippel-Lindau (VHL) gene leading to genetic stabilisation of hypoxia-inducible factor (HIF) transcription factor. The HIF pathway drives tumor development and progression in the VHL–inactivated ccRCC. HIF transcriptionally targets over 100 genes, and the loss of VHL function induces constitutive HIF-1α/2α expression.
Tyrosine kinase inhibitors (TKI) primarily targeting VEGF receptors such as sunitinib are the first-line therapy for treating metastatic ccRCC. Immune checkpoint inhibitors targeting the Cytotoxic T-lymphocyte antigen-4 (CTLA-4) the Programmed Cell Death 1 (PD-1) or its ligand PD-L1 have also been approved as the first-line therapy in some countries.
However, the majority of patients will eventually become resistant to these therapies or are resistant to them. It is therefore necessary to identify these patients and to offer them new therapeutic strategies.
Based on gene expression, methylation status, mutation profile, cytogenetic anomalies, and immune cell infiltration, 4 subtypes of ccRCC patients (ccrcc1–4) have been classified. These markers have prognostic and predictive values for guiding TKI-based therapy. The ccrcc2&3 subtypes possess a good prognosis value of progression free (PFS) and overall survival (OS) and favorable for TKI therapy, whereas the ccrcc1&4 subtypes have the opposite prognostic values with poor prognosis and TKI responses.
Polo-Like Kinase 1 (Plk1) is a serine/threonine kinase that acts during cell cycle progression. Plk1 inhibits p53, and p53 represses the Plk1 promoter. High Plk1 expression correlates with an advanced disease stage, histological grades, metastatic potentials, and short-term survival in various tumors.
However, molecular mechanisms that underlie Plk1 expression are poorly understood.

In this paper, published in Communication Biology and entitled “Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell Renal Cell Carcinoma”, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Volasertib inhibition of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.

This works a work carried out thanks to many collaborations with CNRS UMR7284 / INSERM U1081 team from IRCAN with Dr Gilles Pagès, with many clinicians (oncologists, urologists, pathologist, UroCCR group) from France and Belgium, and zebrafish specialist researcher from Sweden (Karolinska Institute)…



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