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Triple-negative tumours run high on the MYC oncogene, which predicts poor prognosis, and that dependence makes them vulnerable to CDK inhibitors, which shrank MYC-high tumours in mice.
Triple-negative tumours exhibited elevated MYC expression and altered expression of MYC regulatory genes, resulting in increased MYC pathway activity. In primary tumours MYC signalling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. A synthetic-lethal approach dependent on cyclin-dependent kinase inhibition induced regression of triple-negative xenografts; the pro-apoptotic BCL-2 family member BIM was up-regulated after CDK inhibition and contributed to the mechanism.
MYC amplification, present in a fifth to a third of TNBC, is undruggable directly; this is the synthetic-lethal logic behind CDK (especially CDK9 and CDK1/2) inhibitor trials in the disease.
Shares Laura J. Esserman, UCSF Helen Diller Family Comprehensive Cancer Center.
Shares Laura J. Esserman, UCSF Helen Diller Family Comprehensive Cancer Center, Triple-negative breast cancer (TNBC).
Shares Laura J. Esserman, UCSF Helen Diller Family Comprehensive Cancer Center, Triple-negative breast cancer (TNBC).
Shares Laura J. Esserman, UCSF Helen Diller Family Comprehensive Cancer Center.
Shares Synthetic lethality, Triple-negative breast cancer (TNBC).
Shares Laura J. Esserman, UCSF Helen Diller Family Comprehensive Cancer Center, Triple-negative breast cancer (TNBC).
Shares UCSF Helen Diller Family Comprehensive Cancer Center, MYC, Triple-negative breast cancer (TNBC).
Shares UCSF Helen Diller Family Comprehensive Cancer Center, Triple-negative breast cancer (TNBC).