Epigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor

Hormone receptor-positive, HER2-negative advanced breast cancers exhibit high sensitivity to CDK4/6 inhibitors such as palbociclib. However, most patients inevitably develop resistance, thus identification of new actionable therapeutic targets to overcome the recurrent disease is an urgent need. Immunohistochemical studies of tissue microarray revealed increased activation of non-receptor tyrosine kinase, ACK1 (also known as TNK2) in most of the breast cancer subtypes, independent of their hormone receptor status. Chromatin immunoprecipitation studies demonstrated that the nuclear target of activated ACK1, pY88-H4 epigenetic marks, were deposited at cell cycle genes, CCNB1, CCNB2 and CDC20, which in turn initiated their efficient transcription. Pharmacological inhibition of ACK1 using its inhibitor, (R)-9b dampened CCNB1, CCNB2 and CDC20 expression, caused G2/M arrest, culminating in regression of palbociclib-resistant breast tumor growth. Further, (R)-9b suppressed expression of CXCR4 receptor, which resulted in significant impairment of metastasis of breast cancer cells to lung. Overall, our pre-clinical data identifies activated ACK1 as an oncogene that epigenetically controls the cell cycle genes governing the G2/M transition in breast cancer cells. ACK1 inhibitor, (R)-9b could be a novel therapeutic option for the breast cancer patients that have developed resistance to CDK4/6 inhibitors

Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance

Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD

Whole slide image with image analysis of atypical bile duct brushing: Quantitative features predictive of malignancy

Background: Whole slide images (WSIs) involve digitally capturing glass slides for microscopic computer-based viewing and these are amenable to quantitative image analysis. Bile duct (BD) brushing can show morphologic features that are categorized as indeterminate for malignancy. The study aims to evaluate quantitative morphologic features of atypical categories of BD brushing by WSI analysis for the identification of criteria predictive of malignancy. Materials and Methods: Over a 3-year period, BD brush specimens with indeterminate diagnostic categorization (atypical to suspicious) were subjected to WSI analysis. Ten well-visualized groups with morphologic atypical features were selected per case and had the quantitative analysis performed for group area, individual nuclear area, the number of nuclei per group, N: C ratio and nuclear size differential. Results: There were 28 cases identified with 17 atypical and 11 suspicious. The average nuclear area was 63.7 µm2 for atypical and 80.1 µm2 for suspicious (+difference 16.4 µm2; P = 0.002). The nuclear size differential was 69.7 µm2 for atypical and 88.4 µm2 for suspicious (+difference 18.8 µm2; P = 0.009). An average nuclear area >70 µm2 had a 3.2 risk ratio for suspicious categorization. Conclusion: The quantitative criteria findings as measured by image analysis on WSI showed that cases categorized as suspicious had more nuclear size pleomorphism (+18.8 µm2) and larger nuclei (+16.4 µm2) than those categorized as atypical. WSI with morphologic image analysis can demonstrate quantitative statistically significant differences between atypical and suspicious BD brushings and provide objective criteria that support the diagnosis of carcinoma

Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer

Abstract The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of which sensitizes castration-resistant prostate cancer (CRPC) to androgen synthesis inhibitor, Abiraterone. Further, we identify a distinct CRPC lipid signature resembling lipid profile of prostate cancer in African American (AA) men. Overall, pY-SREBF1/H2A-K130ac signaling explains cancer sex bias and reveal synchronous inhibition of KAT2A and Tyr-kinases as an effective therapeutic strategy

Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma

Tumour heterogeneity in clear cell renal cell carcinoma (ccRCC) remains to be investigated. Here, the integration of spatial omics, transcriptional and chromatin accessibility profiling at the single-nucleus level and bulk proteogenomics data reveal markers and pathways important for ccRCC