Résistance aux inhibiteurs des tyrosines kinases dans le cancer du rein

Abstract

FOCUS ON RESISTANCE TO TYROSINE KINASE INHIBITORS IN RENAL CANCER: The last decade has seen significant advances in understanding the biology and genetics of kidney cancer, some of which have radically changed treatment standards, including the emergence of targeted therapies. TKIs have significantly improved outcome in patients with metastatic disease. Nevertheless, a subset of patients (approximately 25 %) does not show any clinical benefit from targeted therapies. In many cases, patients initially respond to therapy but resistance to targeted agents has been shown to develop after a median of 6-12 months of treatment. Two general models of tumor resistance to anti-angiogenic agents targeting the VEGF pathway have been proposed: an adaptive (evasive) resistance, which occurs after a prolonged application of a drug (providing a period of tumor control), or intrinsic one (preexisting) non-responsiveness despite the presence of an active agent, showing no therapeutic benefit. Intrinsic resistance is related to tumor redundancy of pro-angiogenic pathways. Acquired resistance is associated with activation of alternative pathways either by upregulation of the VEGF pathway or by recruitment of alternative angiogenic factors responsible for tumor revascularization. Because different combinations and sequences of TKI are tested in clinical trials and immunotherapy (alone or in combination) radically alters patient management in its metastatic disease, the current effort aims at identifying resistance processes, evaluating their importance and proposing rational therapeutic approaches in order to obtain an additional clinical benefit. Our article summarizes the different mechanisms of resistance described in the literature.

Keywords: Acquired and intrinsic; Cancer du rein; Drug resistance; Inhibiteurs de tyrosine; Metastatic renal cell; Résistance acquise; Résistance intrinsèque; Tyrosine kinase; adaptative; carcinoma; inhibitors; kinase; métastatique; resistance.