The aberrant activation of REarranged during Transfection (RET) proto-oncogene is a driver event for multiple cancers, including medullary thyroid cancer (MTC). Several multi-kinase inhibitors (MKI), not designed to target RET but with biochemical activities against it, have been tested for RET-driven cancers treatment. The limited activities and increased toxicities of MKIs, in part due to their off-target activities, have restricted the use of these drugs. The deepening of knowledge of the RET molecular activation and signaling allowed the design of new selective RET inhibitors. Although these new compounds are showing to be more effective, the development of secondary resistance remains and makes it necessary to develop more specific and potent RET kinase inhibitors. Much is known about RET structure and function, but they still remain many open questions. For example, tyrosine 900 (Y900) is described to be a key autophosphorylation site necessary for the full RET activation. However, we found three patients affected by a severe form of medullary thyroid cancer harboring a somatic deletion including the residue 900, suggesting a possible role of this amino acid in a negative regulatory feedback signaling rather than in RET activation. This project aims to investigate the role of Y900 in RET activation, providing more information about the RET regulatory mechanism. The impact of this information will be relevant in order to design and develop more specific and potent RET kinase inhibitors to be used as new therapeutic strategies for patients with RET-driven tumors. To achieve this goal, we will perform in vitro site-direct mutagenesis experiments and we will analyze the RET signaling using the proteome profiler arrays.
It is well known that aberrant activation of RET is a critical driver of tumor growth and proliferation across a broad spectrum of tumors. Uncovering the structural and molecular determinants of RET kinase activation and its oncogenic deregulation is crucial to design and develop more specific and potent RET kinase inhibitors to be used for patients with RET-driven tumors treatment. Although many attempts have been made to decipher the molecular basis for RET kinase activation, this mechanism has not yet been fully elucidated.
The project aims to improve the knowledge on RET function by investigating the role of tyrosine 900 in its activation and signaling exploiting the in vitro techniques of mutagenesis and the proteome profiler arrays. Our findings will provide useful information for new selective anti-RET drugs design.