Malignant melanoma is a highly aggressive cancer that arises from the transformation of melanocytes, the pigment-producing cells within the basal epidermal layer in human skin. Malignant melanoma accounts for only 5% of all skin cancers, yet is responsible for 80% of skin cancer deaths.While current therapeutic approaches (MEK inhibitors, BRAF inhibitors and immune checkpoint inhibitors) have yielded unprecedented clinical responses, the majority of patients fail to respond or acquire resistance to these treatments. Therefore, investigating the cause of drug resistance is key to the development of better therapies.
Importantly, the Link lab discovered a novel mechanism of resistance to a broad spectrum of drugs in clinical trials/use for melanoma therapy mediated by the kinase-like protein Tribbles homolog 2 (TRIB2).TRIB2 belongs to a wider family of proteins named the TRIBBLES protein family which are highly conserved during evolution. TRIB2 mediates AKT activation resulting in increased MDM2 activity and FOXO inhibition. As a consequence, the expression of FOXO target genes, which could lead to drug induced apoptosis, is attenuated by TRIB2. AKT is an important kinase that belongs to the PI3K pathway, frequently mutated and hperactivated in several human cancers.
This proposal sets out a strategic multidisciplinary approach to (1) characterize the mechanisms involved in TRIB2 mediated resistance to MEK inhibitors and (2) evaluate the clinical relevance of our findings. The expected
results will be clinically relevant as they will allow stratifying patients into responders and non-responders to anticancer agents in a personalized medicine setting, leading to the development of co-treatment strategies.
We have used the gene editing technology, CRISPR-Cas9, to generate TRIB2 Knock-out cells and analyse changes in gene expression dependent on TRIB2 status. Following, we identified compounds capable of reversing TRIB2-mediated resistance. With this approach, these compounds club be potentially be used in the clinic to overcome therapeutic resistance. We found that the naturally occurring alkaloids - Harmine and Piperlongunime -could inverse the gene expression profile induced by TRIB2 expression. Moreover, both compounds are able to promote FOXO nuclear translocation and induce the transcription of FOXO target genes.
