Identification de cibles cellulaires impliquées dans l'hypertension artérielle pulmonaire induite par les inhibiteurs de protéines kinases par une analyse de pharmacovigilance / pharmacodynamie

Abstract : Pulmonary arterial hypertension (PAH) remains a rare and incurable, life-threatening disease, induced by several etiologies. Few drugs are known to induce PAH. Among them, the multi tyrosine kinase inhibitor dasatinib was recently linked to PAH followed by other protein kinases inhibitors (PKI). Nevertheless the pathophysiology of PAH induced by PKI remains unclear. To gain knowledge into this pathology we performed a study combining a pharmacovigilance approach (disproportionality analysis) and the pharmacodynamics properties of PKI. A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib, nilotinib and imatinib. Four non-receptors proteins kinase disclosed a significant correlation with the development of PAH: c-src, c-, Lck and Lyn, all belonging to the SRC family kinases. Moreover, a co-medication analysis revealed that diuretics, insulins, statins and antihypertensive drugs are more frequently associated in dasatinib PAH cases compared to other adverse event cases. Interestingly, in a cluster analysis the dasatinib profile seems different from other PKI. Consistently and based on in vitro and in vivo findings, PKI increase the risk of developing PAH but require a comparable genetic, epigenetic or environmental “second hit”. This is to our knowledge, the first pharmacovigilance analysis which investigate the risk of PAH associated with PKI. The study highlights the role of SRC protein kinases family in PAH induced by PKI. These results have to be confirmed by further studies. Overall, this study contributes to a better understanding of PAH induced by PKI.
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Master Thesis
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Submitted on : Wednesday, June 12, 2019 - 11:40:48 AM
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Lucie Cornet. Identification de cibles cellulaires impliquées dans l'hypertension artérielle pulmonaire induite par les inhibiteurs de protéines kinases par une analyse de pharmacovigilance / pharmacodynamie. Sciences pharmaceutiques. 2018. ⟨dumas-02153482⟩

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