20-30% of breast cancers display a ErbB2 over-expression (BrCa-ErbB2). ErbB2 is a constitutively activated receptor belonging to the EGFR tyrosine kinase receptor family. When over-expressed it triggers the activation of both ERK1/2 and AKT signaling pathways.

Trastuzumab (TZ) and Pertuzumab (PZ) are front line humanized antibodies for the therapy of BrCa-ErbB2; however they face frequent primary or acquired resistance and their mechanism of action is still unclear.

We have shown that TZ and PZ treatment of BrCa-ErbB2 cells induce activation of ERK1/2 and inhibition of AKT, leading cells to G1 arrest. Surprisingly we found interplay between the two events, as ERK1/2 drives the AKT de-phosphorylation. For TZ we excluded a role for the upstream AKT kinase pathway and  identified: 1. an unexpected role for Ser/Thr phosphatases in the TZ-induced ERK1/2-dependent AKT de-phosphorylation; 2. cyclophilin A as negative modulator of the process.

Resistance to TZ is mostly due to impaired inactivation of the AKT pathway, therefore the role of AKT Ser/Thr phosphatases and of cyclophilin A as modulators of TZ activity identifies them as possible molecular targets for the development of new drugs to bypass BrCa-ErbB2 resistance and potentiate TZ activity.

Here we propose a project aiming at: 1. the clarification of the PZ mechanism of action as a tool to identify potential new targets; 2. the screening of FDA approved orphan drugs to hit the TZ identified molecular targets. The candidate will acquire experience in cell and molecular biology, advanced imaging approaches and high throughput screening technologies.

Further information on the host lab can be found on the dedicated web page.