New research from scientists at the Institute for Systems Biology (ISB) and MIT has identified a critical survival mechanism that allows melanoma cells to quickly evade BRAF inhibitor treatments. The study, published in Cell Systems, identified a reversible adaption that can occur within hours of the first treatment and does not rely on reactivating the BRAF-ERK pathway, the most common mechanism of resistance.
The finding is an important piece to gain a better understanding of why BRAF inhibitor drugs like vemurafenib, which initially halt tumor growth, often fail after a short time.
“We found that while the BRAF-ERK signaling pathway was quickly and durably suppressed, cancer cells did not rely on reactivating ERK to survive,” said co-first author Chunmei Liu, PhD, a bioinformatics scientist at ISB. “Instead, they triggered an alternative SRC family kinase (SFK) signaling pathway, which promoted cell survival and eventual recovery.”
Melanoma tumors are often driven by mutations in the BRAF gene. BRAF inhibitors work by blocking this gene’s activity, but their effectiveness is often short-lived. The new study uncovers the role of the SFK signaling pathway that enables melanoma cells to evade treatment before genetic resistance occurs.
To make this discovery, the investigators mapped the changes in melanoma cells’ molecular networks over time using advanced mass spectrometry and transcriptomics. Their findings showed that as melanoma cells are exposed to BRAF inhibitors, they accumulate reactive oxygen species (ROS), which then trigger the SFK pathway. This adaptation allows the cells to survive, but it is reversible. When the treatment is halted, the cells revert to their original state. Recognizing this vulnerability, the team tested a combination therapy, pairing the BRAF inhibitor with the SFK inhibitor dasatinib, and found that it effectively blocked the survival pathway, reducing cell survival and stabilizing tumors in animal models.
“This approach has the potential to prolong the effectiveness of BRAF inhibitors and improve patient outcomes,” said Jim Heath, PhD, ISB president and one of the authors of the paper.
“By adding dasatinib, we blocked this adaptive escape mechanism, significantly reducing melanoma cell survival and stabilizing tumors,” added Wei Wei, PhD, associate professor at ISB.
The research was conducted using a patient-derived melanoma cell line, which showed the early molecular events that allow melanoma cells to survive, including how phosphorylation of key proteins in the signaling networks of melanoma cells was altered during BRAF inhibition. The investigators found that melanoma cells did not reactivate the usual BRAF-ERK signaling pathway but instead relied on the SFK pathway for survival.
These new findings build off earlier studies of cellular behavior to targeted cancer therapies, which have shown that cancer cells can adapt to therapeutic pressure by activating alternative signaling pathways. This study now offers a more detailed picture of the early stages of adaptation—information that can be used to develop new therapeutic approaches to treat melanoma.
In animal models of melanoma, the team showed that SFK inhibition alone had minimal impact on the tumor cells but combining it with BRAF inhibition stabilized the tumors.
Building on this finding, the researchers will conduct additional preclinical studies to explore the role of ROS and SFK in the adaptive survival of melanoma cells and to test the combination therapy in additional melanoma models.
