HDAC8 Activity and Resistance to BRAF Inhibitor Therapy in Melanoma
Posted: Tuesday, May 21, 2019
Melanoma cells adapt to multiple stresses, such as BRAF-MEK inhibition, through histone deacetylase 8 (HDAC8) regulation of stress response pathways. Keiran S.M. Smalley, PhD, of the Moffitt Cancer Center in Tampa, Florida, and a team of researchers recently published this mechanism of resistance in melanoma in Cancer Research. Their findings suggest that the development of HDAC8 inhibitors may prove to be an effective way to improve therapeutic responses.
“Our work provides the first evidence that HDAC8 activity is increased in responses to multiple, diverse cellular stresses, and that this in turn initiates a transcriptional program that is associated with increased melanoma cell survival,” said Dr. Smalley in an institutional press release.
The team conducted a series of experiments utilizing both cell lines and mouse models to determine how melanoma becomes resistant to therapy. Using mass spectrometry–based phosphoproteomics, the team established that HDAC8 was implicated in the regulation of MAPK and AP-1 signaling. Additionally, the introduction of HDAC8 into naive melanoma cells was able to confer resistance to BRAF inhibitors in vivo and in vitro.
The resistance seems to be mediated by receptor tyrosine kinase activation, leading to downstream MAPK signaling. HDAC8 regulates nonhistone substrates, and the introduction of HDAC8 decreases acetylation of c-Jun, thereby increasing the transcriptional ability of c-Jun and promoting the AP-1 gene signature. Xenograft studies confirm that HDAC8 plays a role in the adaptation of melanoma cells, as HDAC8 inhibitors may be able to enhance the durability of previously ineffective BRAF inhibitor therapies.
“These findings provide a strong rationale to pursue the development of more selective and potent HDAC8 inhibitors for future evaluation as drugs that can limit phenotype switching and therapeutic escape in melanoma,” suggested Dr. Smalley.
Disclosure: The study author’s disclosure information can be found at cancerres.aacrjournals.org.