Abstract
BackgroundAlthough MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer.MethodsUsing small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells.ResultsBreast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent.ConclusionsOverall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer is warranted.
Highlights
MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available
Since cellular context and tissue type affect the biological functions of MYC [24] and presumably affect these synthetic lethal interactions, we investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer
We found that targeting cyclin-dependent kinase 1 (CDK1) rather than CDK4/6 or CDK2 selectively reduced the viability of MYC- dependent breast cancer cells, suggesting a potential therapeutic value of targeting CDK1 for MYC-driven human breast cancer
Summary
MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. The key role of MYC activation in the pathogenesis of breast cancer and the high incidence of MYC deregulation make MYC an attractive therapeutic target in breast cancer Transcription factors such as MYC are challenging to target directly and clinically-effective pharmaceutical agents targeting MYC are not yet available [17,18]. Cancer cells develop dependence on other genes and pathways in order to overcome antitumorigenic effects, such as apoptosis and senescence, that result from activation of MYC These dependencies may provide novel therapeutic options for targeting MYC addiction. Since cellular context and tissue type affect the biological functions of MYC [24] and presumably affect these synthetic lethal interactions, we investigated the therapeutic potential of specific CDK inhibition in MYC-driven breast cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
