The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list.
Marasco, M. et al. Cell Rep Med. 5 (11): 101818. (2024).
doi: 10.1016/j.xcrm.2024.101818.
Summary of the findings
Summary of the findingsLoss of neurofibromin (NF1), a negative regulator of RAS signaling, occurs in ~20% of melanoma cases. Unlike BRAF V600E melanoma, no effective targeted therapies exist for these patients if they fail or cannot tolerate immunotherapy.
.
In this paper, Marasco et al. provide a detailed biochemical characterization of how NF1 loss affects oncogenic signaling in melanoma, revealing unique vulnerabilities that can be pharmacologically targeted. The increase in RAS signaling due to NF1 loss is associated not only with increased proliferation but also with compensatory mechanisms that reduce the ability of RAS to be reactivated by external stimuli – an example of a negative feedback loop.
.
Therefore, when both RAS signaling and the ability to reactivate RAS are inhibited, NF1-null melanoma cells experience greater growth inhibition and apoptosis than wild-type cells, as a lower drug concentration is sufficient to prevent RAS reactivation in this tumor type. This study shows that this dual inhibition can be achieved with a combination of avutometinib (a MEK inhibitor) and BI-3406 (a SOS1 inhibitor), which effectively suppresses NF1-null melanoma growth both in vitro and in vivo.
.
Future impact
NF1-null melanoma represents a major unmet clinical need. Despite its higher RAS activity, this tumor is not sensitive to MEK inhibition. Analysis of signaling dynamics revealed a specific dependency of NF1-null melanoma cells on the activity of SOS1 in mediating RAS reactivation following MEK inhibition. Concurrent inhibition of MEK and SOS1 effectively inhibits NF1-null melanoma cell growth and proliferation.
.
The findings presented in this paper provide a strong rationale for the clinical evaluation of the avutometinib + BI-3406 combination as a potential treatment strategy for this tumor type.
.
