Targeting MYC with JQ1 may help treat anaplastic thyroid cancer
Targeting of the MYC protein appears to be an effective approach against anaplastic thyroid cancer (ATC), for which treatment options are limited, according to a recent study.
“Effective treatment of human ATC has long been a challenge for clinical oncologists. Many approaches, including tyrosine kinase inhibitor–based targeting therapies, failed to improve the outcome of patients with ATC. One possible difficulty is the complexity and heterogeneity in the genetic abnormalities underlying ATC,” researchers said. [Anticancer Agents Med Chem 2012;12:87–93; Curr Opin Oncol 2013;25:44–49]
JQ1, a potent inhibitor that effectively disrupts the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin, significantly inhibited the proliferation of four ATC cell lines by suppressing MYC and elevating p21 and p27 to reduce phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 weakens epithelial-mesenchymal transition signals, thereby blocking cell invasion. [J Clin Endocrinol Metab 2017;102:268-2280]
“The four human ATC cell lines used in the present studies harbour complex genetic alterations,” researchers said. “Remarkably, JQ1 treatment was effective in suppressing proliferation and reducing invasion of tumour cells in these four cell lines, albeit with minor quantitative differences in the extent of responses.” [J Clin Endocrinol Metab 2010;95:5338–5347]
Two representative xenograft studies further validated these cell-based analyses, in which JQ1 inhibited the size and rate of tumour growth by hampering p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling.
“These results suggest that targeting chromatin regulators such as BET proteins with JQ1 in these ATC tumour cell lines is effective,” researchers said. “These findings raise the possibility that JQ1 and its next-generation analogues could be beneficial for ATC patients.”
Moreover, JQ1 has been shown to be effective in reducing tumour growth in several myeloid-derived tumours, including acute myeloid leukaemia and multiple myeloma and thyroid anaplastic tumours in mouse models. [Clin Cancer Res 2017;23:430–440; Oncotarget 2015;6:17698–17712; Blood 2012;120:2843–2852; Blood 2014;123:697–705]
“It is tempting to speculate that other oncogenic drivers … in addition to MYC may be inhibited at the transcriptional levels via epigenetic modifications of bromodomain proteins or other components of chromatin-remodeling complexes,” researchers noted. “Determining whether such antagonists can be developed for potential treatment of ATC awaits future studies.”
In the present study, researchers examined the effects of JQ1 on proliferation and invasion in cell line and xenograft tumours, and identified key regulators critical for JQ1-affected proliferation and invasion of tumour cells.
One of the most aggressive cancers in humans, ATC derives from complex and heterogeneous genetic changes that make effective treatment a major challenge. Patients with ATC rarely survive beyond 1 year even though well-differentiated thyroid cancer responds well to radioiodine therapy and usually has a favourable therapeutic response. [J Clin Invest 2016;126:1052–1066]