Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

Menée sur des lignées cellulaires de divers types de cancer et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels un composé appelé SHP099, un inhibiteur de SHP2, exerce une activité antitumorale

Résumé en anglais

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2, 3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071