Yingjun Jiang

Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia

Homoharringtonine (HHT) is a plant alkaloid that inhibits the elongation phase of translation that is currently in clinical trials. Because the intrinsically short-lived antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) has been reported to support the survival of chronic lymphocytic leukemia (CLL) cells, we hypothesized that inhibition of protein synthesis by HHT would decrease Mcl-1 expression and induce apoptosis in CLL. In primary CLL cells, HHT induced significant apoptosis independent of the prognostic characteristics of the patients. This was associated with inhibition of translation and decreased Mcl-1 levels in CLL cells. Mcl-1 reduction was evident as early as 2 hours and continued to decrease in the next 6-8 hours, whereas cell death started in 2 hours and continued to increase for 24 hours. Reduction of the Mcl-1 level was due to translation inhibition and proteasome degradation rather than to transcription inhibition or caspase cleavage. HHT and the transcription inhibitor SNS-032 induced synergistic cell killing. Although stromal cells induced Mcl-1 expression and protected CLL cells from the toxicity of fludarabine, this induction was reversed by HHT, which overcame stromal cell-mediated protection. Thus, these results provide a rationale for clinical development of HHT in CLL as single agent or in combinations.

DNA-Dependent Protein Kinase and Ataxia Telangiectasia Mutated (ATM) Promote Cell Survival in Response to NK314, a Topoisomerase IIα Inhibitor

4-Hydroxy-5-methoxy-2,3-dihydro-1H-[1,3]benzodioxolo[5,6-c]pyrrolo[1,2-f]-phenanthridium chloride (NK314) is a benzo[c] phenanthridine alkaloid that inhibits topoisomerase IIα, leading to the generation of DNA double-strand breaks (DSBs) and activating the G2 checkpoint pathway. The purpose of the present studies was to investigate the DNA intercalating properties of NK314, to evaluate the DNA repair mechanisms activated in cells that may lead to resistance to NK314, and to develop mechanism-based combination strategies to maximize the antitumor effect of the compound. A DNA unwinding assay indicated that NK314 intercalates in DNA, a property that likely cooperates with its ability to trap topoisomerase IIα in its cleavage complex form. The consequence of this is the formation of DNA DSBs, as demonstrated by pulsed-field gel electrophoresis and H2AX phosphorylation. Clonogenic assays demonstrated a significant sensitization in NK314-treated cells deficient in DNA-dependent protein kinase (DNA-PK) catalytic subunit, Ku80, ataxia telangiectasia mutated (ATM), BRCA2, or XRCC3 compared with wild-type cells, indicating that both nonhomologous end-joining and homologous recombination DNA repair pathways contribute to cell survival. Furthermore, both the DNA-PK inhibitor 8-(4-dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one (NU7441) and the ATM inhibitor 2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one (KU55933) significantly sensitized cells to NK314. We conclude that DNA-PK and ATM contribute to cell survival in response to NK314 and could be potential targets for abrogating resistance and maximizing the antitumor effect of NK314.

Mechanism-Based Drug Combinations with the DNA Strand–Breaking Nucleoside Analog CNDAC

CNDAC (2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosyl-cytosine, DFP10917) and its orally bioavailable prodrug, sapacitabine, are undergoing clinical trials for hematologic malignancies and solid tumors. The unique action mechanism of inducing DNA strand breaks distinguishes CNDAC from other deoxycytidine analogs. To optimize the clinical potentials of CNDAC, we explored multiple strategies combining CNDAC with chemotherapeutic agents targeting distinct DNA damage repair pathways that are currently in clinical use. The ability of each agent to decrease proliferative potential, determined by clonogenic assays, was determined in paired cell lines proficient and deficient in certain DNA repair proteins. Subsequently, each agent was used in combination with CNDAC at fixed concentration ratios. The clonogenicity was quantitated by median effect analysis, and a combination index was calculated. The c-Abl kinase inhibitor imatinib had synergy with CNDAC in HCT116 cells, regardless of p53 status. Inhibitors of PARP1 that interfere with homologous recombination (HR) repair or base excision repair (BER) and agents such as temozolomide that cause DNA damage repaired by the BER pathway were also synergistic with CNDAC. The toxicity of the nitrogen mustards bendamustine and cytoxan, or of platinum compounds, which generate DNA adducts repaired by nucleotide excision repair and HR, was additive with CNDAC. An additive cell killing was also achieved by the combination of CNDAC with taxane mitotic inhibitors (paclitaxel and docetaxel). At concentrations that allow survival of the majority of wild-type cells, the synergistic or additive combination effects were selective in HR-deficient cells. This study provides mechanistic rationales for combining CNDAC with other active drugs. Mol Cancer Ther; 15(10); 2302–13. ©2016 AACR.

Abstract 3528: Quantitation of ATM function in primary CLL cells.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal B-cell development in which mechanisms for cell death have been altered. As the second most common type of leukemia in adults, it progresses at a very slow rate compared to other leukemias and is considered incurable. Approximately 10% of previously untreated patients with CLL exhibit a substantial deletion in the q arm of chromosome 11 (11q22.3), the site of the ATM gene (ataxia telangiectasia mutated). Deletion of this region is associated with rapid disease progression and shorter overall survival. This lesion occurs at increased incidence, 40-50%, in patients who relapse on fludarabine-cyclophosphamide-rituximab chemoimmunotherapy. The residual ATM allele is often mutated, suggesting that the region containing ATM is important for response to chemotherapy. Also, because ATM is critical for repairing double strand breaks that arise after exposure to PARP1 inhibitors and drugs that cause replication fork collapse, identification of tumors that lack ATM function may be a biomarker for specific therapies. In order to distinguish CLL disease with ATM non-functional and functional among del(11q22.3) patients characterized by fluorescence in situ hybridization (FISH), we have established an assay of ATM activity in primary CLL cells. It is known that ATM is activated in response to ionizing radiation and will further phosphorylate its downstream targets. We have demonstrated that phosphorylation of KAP1 and Smc1 (both ATM downstream substrates) are primarily dependent on the activity of ATM using cell lines established from a patient with ataxia telangiectasia that are either deficient in ATM function or complemented with the full length gene. In this assay, CLL samples from eight patients with normal FISH karyotype were collected, mock treated or irradiated with a 10 Gy dose, and protein lysates were prepared. The lysates were then combined as a positive pool comparator for the del(11q22-23) CLL samples, and both total and phosphorylated KAP1 and Smc1 proteins were quantitated by immunoblotting. The averaged phosphorylation levels of the KAP1 and Smc1 proteins among the irradiated samples from patients with del(11q22.3) by FISH was calculated and compared with those of the ATM-positive pool. An averaged phosphorylation ratio ≤30% of the positive pool sample was taken as indicative of a deficiency in ATM function. Using this cutoff, we identified five ATM non-functional individuals among ten del(11q22.3) CLL samples isolated from archived stocks. The mutation status of DNA extracted from CLL cells is being analyzed by deep sequencing in reference to the subjects’ T-cell genomic DNA . This assay could be applied to CLL and other tumors at risk for loss of ATM activity, to identify those deficient in ATM function. These individuals may be considered for tumor-specific and personalized therapy targeting ATM deficiency. Citation Format: Yingjun Jiang, Xiaojun Liu, Sijin Wen, Kim-Anh Do, Xiaoping Su, Michael J. Keating, William Wierda, William Plunkett. Quantitation of ATM function in primary CLL cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3528. doi:10.1158/1538-7445.AM2013-3528

Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations

PurposeThe mechanism of action of CNDAC (2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosyl-cytosine) is unique among deoxycytidine analogs because upon incorporation into DNA it causes a single strand break which is converted to a double strand break after DNA replication. This lesion requires homologous recombination (HR) for repair. CNDAC, as the parent nucleoside, DFP10917, and as an oral prodrug, sapacitabine, are undergoing clinical trials for hematological malignancies and solid tumors. The purpose of this study is to investigate the potential of CNDAC for the therapy of ovarian cancer (OC).MethodsDrug sensitivity was evaluated using a clonogenic survival assay. Drug combination effects were quantified by median effect analysis.ResultsOC cells lacking function of the key HR genes, BRCA1 or BRCA2, were more sensitive to CNDAC than corresponding HR proficient cells. The sensitization was associated with greater levels of DNA damage in response to CNDAC at clinically achievable concentrations, manifested as chromosomal aberrations. Three classes of CNDAC-based drug combinations were investigated. First, the PARP1 inhibitors, rucaparib and talazoparib, were selectively synergistic with CNDAC in BRCA1/2 deficient OC cells (combination index < 1) at a relatively low concentration range. Second, cisplatin and oxaliplatin had additive combination effects with CNDAC (combination index ~ 1). Finally, paclitaxel and docetaxel achieved additive cell-killing effects with CNDAC at concentration ranges of the taxanes similar for both BRCA1/2 deficient and proficient OC cells.ConclusionsThis study provides mechanistic rationales for combining CNDAC with PARP inhibitors, platinum compounds and taxanes in ovarian cancer lacking BRCA1/2 function.

Abstract 4633: The DNA strand breaking nucleoside analogue sapacitabine sensitizes Brca2-deficient ovarian cancer cells and synergizes with PARP inhibitors

Sapacitabine, an orally bioavailable prodrug of the deoxycytidine analog, CNDAC, is currently in a Phase III registration trial for elderly AML patients (NCT01303796). CNDAC (as DFP-10917) is in a Phase I/II trial for relapsed or refractory acute leukemia (NCT01702155) with very limited toxicity. CNDAC-induced DNA damage, double-strand breaks converted from initial single-strand breaks, is repaired mainly by the homologous recombination (HR) pathway. Deficiency in HR components (e.g. ATM, Rad51, Xrcc3, Brca1 and Brca2) confers sensitivity to CNDAC. Brca1/2 function is frequently compromised in ovarian cancer (OC). To determine the role of Brca2 in DNA damage repair after CNDAC, we used in this study a Brca2-mutant ovarian adenocarcinoma cell line, PEO1 and its revertant line, PEO1 C4-2, in which Brca2 function is restored due to a secondary mutation. First, the clonogenic sensitivities of the two lines to therapeutic agents were compared. The mutant was 6-10 fold more sensitive to CNDAC than the revertant. In contrast, Brca2 restoration did not confer resistance to cytarabine or gemcitabine, confirming the unique action mechanism of CNDAC among nucleoside analogs. Second, CNDAC-induced chromosome damage was compared in both lines. We found Brca2- mutant cells bearing more chromosomal structural abnormalities (67% metaphases with scorable breaks or fusions, N = 51) than Brca2-restored cells (14%, N = 50), apparently due to genetic instability when lacking Brca2. The mutant cells exposed to 25 nM CNDAC for 3d manifested massive chromosomal aberrations (100% metaphases unscorable, N = 51). In contrast, the revertant cells showed significantly fewer chromosome aberrations (30% scorable, N = 50). These results provided cytogenetic evidence for Brca2 involvement in DNA damage repair after CNDAC. Third, the combination effect of CNDAC with two classes of front-line anti-OC drugs, platinum compounds and taxanes, was explored using clonogenic assays and median effect analyses. Both cisplatin and oxaliplatin each had additive cell killing effects with CNDAC (combination index, CI ∼1) independent of Brca2 status. Similarly, CNDAC was additive with either paclitaxel or docetaxel in both lines (CI ∼1). Finally, two PARP inhibitors (PARPis), rucaparib and talazoparib, greatly sensitized Brca2-mutant cells. Despite the distinctive sensitivities of the two lines, both rucaparib-CNDAC and talazoparib-CNDAC combinations showed synergistic killing effect (CI Citation Format: Xiaojun Liu, Yingjun Jiang, Billie Nowak, Bethany Qiang, Nancy Cheng, William Plunkett. The DNA strand breaking nucleoside analogue sapacitabine sensitizes Brca2-deficient ovarian cancer cells and synergizes with PARP inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4633.

Abstract 408: ATM function and mutation in CLL 11q deletion samples

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal B-cell development in which cell death mechanisms have been altered. As the second most common type of leukemia in adults, it progresses more slowly than other types of leukemia and is considered incurable. Approximately 10% of previously untreated patients with CLL exhibit a substantial deletion in the q arm of chromosome 11(22-23), the site of the ATM gene, the product of which regulates homologous recombination repair of double strand DNA breaks (DSB). This lesion occurs at increased incidence, about 50% in patients relapsing on fludarabine-cyclophosphamide-rituximab (FCR) therapy. The residual ATM allele is often mutated, suggesting that the region containing ATM is important for response to chemoimmunotherapy. Although some mutations that cause non-synonymous substitution of amino acids associated with loss of ATM function are known, because the ATM protein contains more than 3,000 amino acids, it is unlikely that all most or all non-synonymous changes would cause loss of function. To address this issue, we developed an immunoblot assay to determine ATM function in del(11q22-23) samples from CLL patients. We confirmed that SMC1 and KAP1 are unique substrates of ATM. Their phosphorylation levels after irradiation (IR) were linearly correlated with ATM activity. This was demonstrated using cell lysates mixtures from cells derived from an individual with ataxia telangiectasia that are deficient in ATM, and those cells repleted with ATM. Consequently, the ratios of phospho to total proteins of SMC1 and KAP1 were employed as indicators of ATM function in response to IR treatment. Using a pool made up of lysates from FISH-negative CLL samples (n = 8) as a positive standard, we validated this assay in 46 del(11q22-23) CLL samples. The phosphorylation ratios of SMC1 and KAP1 from 46 CLL samples were analyzed simultaneously by the normal mixture model-based clustering method, and a formula was generated to determine ATM function. Using this formula, we identified 13 ATM function-deficient samples. To determine whether there is a correlation between ATM gene mutation and the function of the protein, we conducted targeted sequencing of the ATM gene in the 46 samples. Genomic DNA of T-cells isolated and expanded from each of these samples was extracted to serve as a germline reference for the CLL cells. Through a series of bioinformatics analyses, 12 different ATM somatic mutations were identified. Fifteen other ATM mutations were recognized as germ line mutations. No strong correlation was observed between ATM mutation and function. Therefore, alternative assays of ATM function, such as that we have described, are needed to identify ATM deficient tumors in order to develop selective therapies, e.g. agents that cause DSB or inhibit redundant repair pathways. Citation Format: Yingjun Jiang, Xiaojun Liu, Hsiang-Chun Chen, Kim-Anh Do, Xiaoping Su, William Wierda, Michael Keating, William Plunkett. ATM function and mutation in CLL 11q deletion samples. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 408.

Abstract 2551: Brca1-deficient ovarian cancer cells are sensitized to the DNA-strand-breaking nucleoside analog sapacitabine that synergizes with PARP inhibition

Sapacitabine is an orally bioavailable prodrug of the deoxycytidine analog, CNDAC. Sapacitabine is currently in a Phase III registration trial for elderly AML patients (NCT01303796). CNDAC (as DFP-10917) is in a Phase I/II trial for AML and ALL (NCT01702155). Sapacitabine/CNDAC-induced DNA damage, double-strand breaks converted from initial single-strand breaks, is repaired mainly by the homologous recombination (HR) pathway. Deficiency in HR components, including ATM, Rad51, Xrcc3, Brca2 and Brca1, confer sensitivity to CNDAC. Brca1 and Brca2 function is frequently compromised in ovarian cancer. To determine the role of Brca1 in DNA damage repair after sapacitabine, we used a Brca1-null ovarian carcinoma cell line, UWB1.289 and its complemented line, UWB1.289+Brca1 in this study. First, the clonogenic sensitivities of the two lines to therapeutic agents were compared. The deficient cells were 3-4 fold more sensitive to CNDAC than the repleted cells. In contrast, Brca1 repletion did not confer resistance to cytarabine, fludarabine or gemcitabine. These results confirm the unique action mechanism of CNDAC among nucleoside analogs. Second, a cytogenetic approach was taken to compare CNDAC-induced chromosome damage in both lines (N = 50 metaphases scored for each sample). We found Brca1-null cells bearing more chromosomal structural abnormalities (∼50% metaphases) than Brca1-complemented cells (∼30%), apparently due to genetic instability when lacking Brca1. UWB1.289 cells exposed to 15 nM CNDAC for 27 hr (1 cell cycle) and 54 hr (2 cell cycles) manifested massive chromosomal aberrations (>60% and >90% metaphases, respectively), nearly 40% and 70% of which could not be scored. In contrast, UWB1.289+Brca1 cells showed significantly fewer chromosome aberrations (42% and 48% metaphases, respectively), the majority of which were scorable, upon extended incubation with CNDAC under the same conditions. These results provided cytogenetic evidence for Brca1 involvement in DNA damage repair after CNDAC. Third, interaction between sapacitabine and other classes of therapeutic agents was explored using clonogenic assays. For example, CO-338, a camsylate salt of the PARP inhibitor, rucaparib, greatly sensitized Brca1-deficient cells. Despite the distinctive sensitivities of the two lines, the CO-338 - CNDAC combination showed synergistic cell killing by median-effect analysis (combination index Citation Format: Xiaojun Liu, Yingjun Jiang, Billie Nowak, Dariya Tikhomirova, William Plunkett. Brca1-deficient ovarian cancer cells are sensitized to the DNA-strand-breaking nucleoside analog sapacitabine that synergizes with PARP inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2551. doi:10.1158/1538-7445.AM2015-2551

Abstract 2550: FANCA protein is involved in the homologous recombination repair of sapacitabine-induced DNA damage

Fanconi anemia (FA) is an autosomal disorder characterized by developmental abnormalities, early-onset bone marrow failure, and a predisposition to cancer. FA cells are defective in DNA repair, and exhibit hypersensitivity to DNA interstrand cross-links (ICLs) and a high degree of chromosomal aberrations. A majority of the FA proteins have been shown to act as signal transducers and scaffolding proteins to employ other pathways to repair DNA. Specifically the FA group A (FANCA) protein has been indicated as an integral component in the early step of homologous recombination (HR) of double strand breaks (DSB). Sapacitabine, the orally bioavailable prodrug of the nucleoside analog CNDAC, has presented favorable clinical activity in advanced acute leukemias and myelodysplastic syndromes. CNDAC kills cells by a unique mechanism of action. Incorporation of CNDAC triphosphate into DNA results in a beta elimination reaction that causes single-strand break (SSB) that is terminated by the analogue. DNA replication over this nick converts the nick to a one-ended double-strand break (DSB) upon collapse of the DNA replication fork. The CNDAC-induced DSBs, which are potentially lethal, are repaired predominantly through homologous recombination (HR), relative to other repair pathways, such as base excision repair, transcription-coupled nucleotide excision repair and non-homologous end-joining. CNDAC greatly sensitizes cells lacking HR components, such as ATM, RAD51D, XRCC3 and BRCA2. Based on the evidence that FANCA associates with proteins involved with HR, we hypothesize that loss of FANCA may also sensitize cells to CNDAC. FANCA-deficient cells from an individual with Fanconi anemia as well FANCA repleted cells were utilized to investigate the role of the FANCA protein in the repair of damage caused by CNDAC. Cells were treated with CNDAC or mitomycin C (MMC), a crosslinking agent. We found that FANCA deficient cells were sensitized to CNDAC about 5-fold as compared with FANCA repleted cells, while they were sensitized by 6-fold when treated with MMC. Cells were treated with 1 μM CNDAC for either 24 or 48 hr before chromosome spread samples were collected to examine the genome integrity. Chromosome aberrations were increased in response to CNDAC treatment, and cells lacking FANCA protein exhibited more chromosomal abnormalities compared with FANCA repleted cells. Rad51 foci, diagnostic indicators of active HR, were present in both lines after 24 or 48 hr of CNDAC treatment; however, FANCA deficient cells displayed attenuated accumulation of Rad51 foci in response to CNDAC as compared with the FANCA repleted cells. These findings indicate that FANCA is involved in the HR repair of CNDAC-induced DNA lesions. Because FANCA is one component of the core complex of the Fanconi repair pathway, other proteins in this group may confer similar sensitization. Citation Format: Yingjun Jiang, Xiaojun Liu, William Plunkett. FANCA protein is involved in the homologous recombination repair of sapacitabine-induced DNA damage. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2550. doi:10.1158/1538-7445.AM2015-2550

Abstract 5454: Inhibition of Bcr-Abl tyrosine kinase sensitizes cells to sapacitabine

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA CNDAC, the active form of sapacitabine, is a nucleoside analog which kills cells by a unique mechanism of action. Incorporation of CNDAC triphosphate into DNA results in a single-strand break, which is converted to a one-ended double-strand break (DSB) upon subsequent collapse of the DNA replication fork. CNDAC-induced DSBs are repaired predominantly through the homologous recombination pathway which consists the key recombinase Rad51 and its associated proteins. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm; its central pathogenesis is a reciprocal chromosomal translocation between chromosomes 9 and 22. This abnormal chromosomal fusion results in the formation of a chimeric gene that encodes a constitutively active tyrosine kinase, Bcr-Abl, which promotes CML through stimulating downstream signaling cascades for cell survival and deregulated cell growth. Bcr-Abl tyrosine kinase modulates DNA repair mechanisms to protect leukemic cells from DNA damage induced cell death. In response to DSBs, it phosphorylates Rad51 at Tyr315 which enhance the damage repair process. Based on this evidence, we hypothesized that inhibition of Bcr-Abl will further sensitize cells to CNDAC. To test this postulate, we used the CML cell line K562 as well as murine Ba/F3 cells transfected with wild-type Bcr-Abl (Ba/F3p210wt) or the Bcr-Abl mutant (Ba/F3p210T315I) as model systems. Two tyrosine kinase inhibitors (TKI) were utilized to inhibit Bcr-Abl. Imatinib, the first generation TKI, is only effective inhibiting wild type Bcr-Abl. Ponatinib, a subsequent TKI, is potent in inhibiting both wild type and mutant Bcr-Abl tyrosine kinases. First, these cells were treated with CNDAC, imatinib or ponatinib alone to determine the IC50 values for each drug using PrestoBlue cell viability assay. Based on the single drug IC50s, combinations of CNDAC with imatinib or ponatinib were applied to these cell lines and their combination indexes were calculated by CalcuSyn software. We found that CNDAC and imatinib were synergistic in K562 and Ba/F3 wild type Bcr-Abl cells while they were additive in the Bcr-Abl T315I mutant cells. In contrast, ponatinib sensitized CNDAC treatment as their combination was synergistic in all these cell lines. Finally, to investigate the mechanism underlying the observed synergism, K562 cells were treated with either equitoxic concentrations of CNDAC, imatinib or ponatinib alone or in combinations for 48 hours when lysates were collected for immunoblot analysis. It was found that when Bcr-Abl was inhibited, the phosphoryation of Rad51 at Tyr315 was reduced, phospho H2AX and cleaved caspase 3 were increased in response to CNDAC. Thus further sensitization of CNDAC was a result of deficient damage repair due to Bcr-Abl inhibition. Together, our results link the Bcr-Abl tyrosine kinase to CNDAC-induced DNA damage repair process and provide rationale for CNDAC/sapacitabine combination therapy in diseases such as CML. Citation Format: Yingjun Jiang, Xiaojun Liu, Adrienne Chestang, William Plunkett. Inhibition of Bcr-Abl tyrosine kinase sensitizes cells to sapacitabine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5454. doi:10.1158/1538-7445.AM2014-5454