We are actively studying the molecular mechanisms mediating drug resistance in melanoma. Our team is particularly interested in the role of the RAF/MEK/ERK pathway as therapeutic target and the mechanisms underlying resistance to inhibitors that block these signaling cascades. Our research is currently focused on 3 interrelated projects:
1. Mechanisms of resistance to BRAF/MEK inhibitors in melanoma.
We have developed laboratory models that show how melanoma gains resistance to BRAF inhibitors. Using these models, we have recently demonstrated that melanoma cells treated with RAF inhibitors find a way to bypass the effects of the drugs by activating alternative signaling pathways. Resistance to BRAF inhibitors involves dynamic RAF kinase switching leading to reactivation of the MAPK pathway and activation of receptor tyrosine kinases, which promote survival of the resistant cells.
As melanoma is a highly heterogeneous disease, multiple mechanisms of resistance are likely to arise in patients. We are now using an array of biochemical and genetic approaches to identify additional mechanisms of resistance and testing combinations of different inhibitors targeting the resistant pathways. Our goal is to identify the best combination therapies that can overcome resistance to BRAF/MEK inhibitors and could move forward into clinical trials.
2. Preclinical evaluation of effective combinations to overcome therapy resistance.
We are delineating genetic and signaling network alterations to guide therapy and assess the best combination therapies that can elicit durable responses in tumors with a given genetic background. Drug combinations are tested first in 3D-tumor spheroids, which more closely mimic the in vivo behavior of melanoma. Selected drug combinations will then be tested in vivo in xenograft and genetic engineered mouse models.
3. Delineating the role of tumor heterogeneity modulating response to therapy.
The limited efficacy of selective RAF inhibitors can also be related to the molecular heterogeneity of melanoma. While treatment with RAF inhibitors may kill a large percentage of tumor cells, it can select for intrinsically resistant tumor cells which may then acquire additional (genetic or epigenetic) properties and promote tumor relapse. The goal of this project is to understand how intra tumor heterogeneity modulates response to therapy and contributes to drug resistance. Our studies aim to understand the molecular basis of tumor heterogeneity as driver of drug resistance and identify pathways that are essential for survival of resistant subpopulations and could provide potential therapeutic targets.