Dr. Olivier E. Pardo, Division of Cancer at Imperial College (London, UK)

Selective targeting of S6 kinase family members for the treatment of cancer, including osteosarcoma

“Our lab has worked for many years on identifying the biological functions of a kinase family called the S6 kinases. We especially worked on members of two subfamilies: the S6Ks (S6K1 and 2 in human) and the RSKs (RSK1 to 4 in human). We demonstrated that S6K2 was involved in the development of drug resistance in cancer through promoting the translation of pro-survival proteins, such as the anti-apoptotic family members of the BCL2 family and IAPs. This was mediated through phosphorylation of a novel S6K2 substrate, the RNA-binding protein, hnRNPA1. Phosphorylation of this protein promoted its interaction with target mRNAs in the nucleus, followed by export of the complex into the cytoplasm for targeted translation. This activity was specific to S6K2, as its close homolog S6K1 (84% homology in the kinase domain) did not regulate cell survival nor phosphorylated hnRNPA1. Our collaborators developed the first-in-class selective S6K2 kinase inhibitor, and we now show that this molecule reproduces in cells the phenotypic effects of knocking-down S6K2 expression and is well tolerated in mice. In contrast to S6K2, RSK4 mediated drug resistance and metastatic potential of cancer cells through regulating the transcription of anti-apoptotic family members of the BCL2 family and IAPs and the NFkB pathway, respectively. This activity was very selective to RSK4 as RSK1, that shares ~85% identity with RSK4, had the opposite biological effects. This biological specificity drove us to identify a selective inhibitor for RSK4 which reproduced in vitro and in vivo all anti-tumoral activities of genetically knocking down RSK4 expression. Interestingly, we subsequently found that S6K2 and RSK4 activities converge at the level of hnRNPA1 as RSK4’s activity is required for hnRNPA1 to exit the nucleus. Finally, we are currently investigating the effect of targeting these three proteins in osteosarcoma, and our preliminary data show that they regulate sensitivity to chemotherapy, response to anti-cancer immune-mediated cytokines and fibroblast activation by cancer cells. We therefore expect that therapeutic targeting of this pathway will be beneficial to the management of several cancer types, including osteosarcoma.”