The Compound Library chaperone heat shock protein 90. Vorinostat induces HSP90 hyperacetylation and inhibits its chaperone function. Thus, vorinostat may inhibit the growth of BCR-ABL-positive cells by changing BCR-ABL conformation via acetylation and inhibition of the chaperone protein HSP90. Phosphorylated cH2A.X is associated with early DNA damage and repair processes that occur in response to double-strand breaks in eukaryotic cells. Vorinostat induced growth arrest and apoptosis, thus aggravating the apoptotic and cytotoxic effects of ponatinib on Ba/F3 T315I mutant cells. Since imatinib inhibits STAT5 phosphorylation as well as the expression of STAT5 target genes, ponatinib may exhibit the same inhibitory effect. In our immunoblot assay, cH2A.X phosphorylation was detected after co-treatment with ponatinib and vorinostat. Co-treatment with ponatinib and vorinostat resulted in increased cytotoxicity and provided strong evidence that vorinostat augments ponatinibinduced apoptosis by enhancing DNA damage responses in BCRABL-positive cells. Patients with hematological malignancies, including Ph-positive leukemia, often AB1010 develop resistance to TKIs. In our study, we used Ba/F3 AP-R BCR-ABL cells and primary samples. We demonstrated that co-treatment with ponatinib and vorinostat reduced the proliferation of ponatinib-resistant cells. Therefore, ponatinib and vorinostat may affect the activity of BCR-ABL and increase antileukemic activity against BCR-ABL mutant cells. Recently, the use of ponatinib has been evaluated in other hematological malignancies and its use has been approved by the FDA. We previously isolated primary cells highly resistant to ponatinib showing several BCR-ABL point mutations. Thus, ponatinib resistance seems to be a possible concern in near future, and therefore, methods to overcome ABL TKI resistance need to be developed. In summary, our results provide new information on the molecular events underlying the antitumor activity of ponatinib and the HDAC inhibitor vorinostat. Co-treatment using these compounds together with molecular-targeted drugs will benefit those with BCR-ABL leukemic cells that are resistant to conventional treatments. Breast cancer is the second-leading cause of cancer death and morbidity among women worldwide. Gene expression profiling has revealed that breast cancer is a heterogeneous entity, and four primary molecular subgroups have been proposed: basal-like, luminal A, luminal B and human epidermal growth factor receptor 2 -overexpressed. Estrogen receptor /HER2positivebreast cancer belongs to the luminal B subtype and accounts for 20�C25% of all breast cancer cases. Studies have shown that ER+/HER2+ patients have a poor prognosis. In contrast to ER-positive/HER2-negtive breast cancer, ER+/HER2+ patients are less responsive to selective estrogen receptor modulators, such as tamoxifen, and to aromatase inhibitors. Recent studies have demonstrated that bidirectional crosstalk between ER and HER2 leads to endocrine resistance in ER+/ HER2+ breast cancer. Agents that block HER2, such as trastuzumaband lapatinib,improve the inhibitory effects of SERMs in ER+/HER2+ cancer. However, nearly 50% of ER+/HER2+ patients show no response. Furthermore, primary or acquired resistance to trastuzumab has been recognized as a major obstacle in the treatment of this disease. Several clinical trials have shown that combining HER2 inhibitors with SERMs improved progression-free survival but did not extend overall survival. Consequently, there is a significant need for elucidating the molecular signaling pathways that promote ER+/HER2+ breast cancer to enable the development of novel therapeutics. Interfering with the growth factor-driven signaling pathways and downstream effector.