ACK1/TNK2 Epigenetically Regulates Cell Cycle Program to Promote Breast Cancer Resistance to CDK4/6 inhibitor
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PROVIDER: PRJNA839095 | ENA |
REPOSITORIES: ENA
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Project description:Over-activation of oncogenes by aberrant expression of epigenetic modulators, overcoming cell cycle checkpoints and bestowing infinite multiplication potency acts as the mainstay of malignancy. We identified one such non-receptor tyrosine kinase ACK1 as an epigenetic regulator of cell cycle genes governing the G2/M transition of breast cancer cells. ACK1 was found to be over-activated (pY264-ACK1) in most of the breast cancer sub-types, independent of their hormone receptor status, as assessed by the Tissue-microarray analysis of nearly 400 breast cancer patient samples. ACK1 primed the epigenetic landscape surrounding the genes CCNB1, CCNB2 and CDC20 by depositing Y88-H4 histone activation marks, in turn initiating their efficient transcription. Pharmacological inhibition of ACK1 using small molecular inhibitor (R)-9b not only reversed this transcriptional potential but also sensitized the cells to a G2/M arrest, culminating in breast cancer cell death and tumor regression in in vivo xenograft models of breast cancer. Further, ACK1 was also found to modulate expression of the gene CXCR4, circumventing breast cancer metastasis on ACK1 ablation. In addition, ACK1 inhibition was also found to counteract the resistance of RB1 deficient breast cancer cells to the CDK4/6 inhibitor palbociclib, overcoming road blocks to conventional therapeutics. Overall, our data warrants the identification of ACK1 as an epigenetic controller of genes essential for the successful establishment and progression of breast cancer and signifies development of therapeutics against ACK1 to combat intrinsic and acquired breast cancer resistance.
2023-05-23 | GSE203231 | GEO
Project description:Over-activation of oncogenes by aberrant expression of epigenetic modulators, overcoming cell cycle checkpoints and bestowing infinite multiplication potency acts as the mainstay of malignancy. We identified one such non-receptor tyrosine kinase ACK1 as an epigenetic regulator of cell cycle genes governing the G2/M transition of breast cancer cells. ACK1 was found to be over-activated (pY264-ACK1) in most of the breast cancer sub-types, independent of their hormone receptor status, as assessed by the Tissue-microarray analysis of nearly 400 breast cancer patient samples. ACK1 primed the epigenetic landscape surrounding the genes CCNB1, CCNB2 and CDC20 by depositing Y88-H4 histone activation marks, in turn initiating their efficient transcription. Pharmacological inhibition of ACK1 using small molecular inhibitor (R)-9b not only reversed this transcriptional potential but also sensitized the cells to a G2/M arrest, culminating in breast cancer cell death and tumor regression in in vivo xenograft models of breast cancer. Further, ACK1 was also found to modulate expression of the gene CXCR4, circumventing breast cancer metastasis on ACK1 ablation. In addition, ACK1 inhibition was also found to counteract the resistance of RB1 deficient breast cancer cells to the CDK4/6 inhibitor palbociclib, overcoming road blocks to conventional therapeutics. Overall, our data warrants the identification of ACK1 as an epigenetic controller of genes essential for the successful establishment and progression of breast cancer and signifies development of therapeutics against ACK1 to combat intrinsic and acquired breast cancer resistance.
2023-05-23 | GSE203230 | GEO
Project description:ACK1/TNK2 Epigenetically Regulates Cell Cycle Program to Promote Breast Cancer Resistance to CDK4/6 inhibitor (RNA-Seq)
| PRJNA839097 | ENA
Project description:ACK1/TNK2 Epigenetically Regulates Cell Cycle Program to Promote Breast Cancer Resistance to CDK4/6 inhibitor (ChIP-Seq)
| PRJNA839098 | ENA
Project description:Solid tumors are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of the effector T cells and its trafficking back to the tumor. The T cell activation is negatively regulated by C-terminal Src kinase (CSK), however, the exact mechanism of CSK’s T cell-restraining activity remains unknown. Here, we show that the primeval oncogenic tyrosine kinase, ACK1 dampens T-cell response by augmenting CSK activity through a novel Tyr18-phosphorylation. Ack1/Tnk2-knockout mice exhibited a loss of CSK Tyr18-phosphorylation and activation of CD8+ and CD4+ T cells, compromising ICB-resistant tumor growth. Further, ICB-treated Castration-resistant prostate cancer (CRPC) patients revitalized ACK1/pY18-CSK signaling, revealing it to be the critical molecular mechanism for ICB insensitivity. Consistently, ICB-resistant tumor growth was suppressed upon treatment with a new class of ACK1 small-molecule inhibitor, (R)-9b. Interestingly, (R)-9b caused increase in leukocyte attractant, CXCL10 in cancer cells, thus navigating newly activated T cells to the tumors, creating a `self-sabotaging loop’. Overall, harnessing unique dichotomous mode of ACK1 that controls immune response of the T cells, and cytokine levels in tumor microenvironment, provides an unprecedented opportunity to sensitize immune-resistance.
2022-09-01 | GSE211835 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-05-23 | GSE203232 | GEO
Project description:T Cell Reinvigoration upon ACK1/TNK2 inhibition Overcomes Immune Resistance
| PRJNA872199 | ENA
Project description:Non-receptor tyrosine kinases represent an important class of signaling molecules which are involved in driving diverse cellular pathways. Although the large majority have been well-studied in terms of their protein binding partners, the interactomes of some important non-receptor tyrosine kinases such as TNK2 (also known as activated Cdc42-associated kinase 1 or ACK1) have not been systematically investigated. Aberrant expression and hyperphosphorylation of TNK2 have been implicated in a number of cancers, although the exact proteins and cellular events that mediate phenotypic changes downstream of TNK2 are unclear. Biological systems that employ proximity-dependent protein labeling methods, such as biotinylation identification (BioID), are being increasingly used to map protein-protein interactomes as they provide increased sensitivity in finding interaction partners. In the present study, we employ BioID coupled to a Biotinylation Site Identification Technology (BioSITe) method we recently developed to perform molecular mapping of intracellular protein interactors of TNK2. By performing a controlled comparative analysis between full-length TNK2 and its truncated counterpart, we were not only able to confidently identify site-level biotinylation of previously well-established TNK2 binders and substrates, but also several novel binders of TNK2 that may help explain its role in oncogenic signaling.
2021-08-25 | PXD010474 | Pride
Project description: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 pY18 phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.
2023-03-11 | PXD037546 | Pride
Project description:Resistance to neoadjuvant chemotherapy is associated tumor recurrence of locally advanced rectal cancer (LARC), which remains an unmet demand to exploit potential therapeutic strategies to improve clinical outcomes. Here we demonstrated that aberrant activation of cell cycle pathways is correlated with resistance to neoadjuvant chemotherapy in LARC. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators with oxaliplatin identified that CDK4/6 inhibitors synergistically enhanced anti-tumor effects of oxaliplatin both intrinsic and acquired chemo-resistant colon cancer cells. Functional studies in both in vitro and in vivo models showed that CDK4/6 inhibitors significantly increased sensitivity to oxaliplatin. Integrative transcriptomic and chromatin profiling analysis revealed that CDK4/6 inhibitors induced DNA repair defects to enhance sensitivity of oxaliplatin through epigenetically suppression of DNA repair related genes. Mechanistically, CDK4/6 inhibition impairs DNA damage repair through a previously unrecognized RB1/TEAD4/HDAC1 co-repressor complex which contributes to the resistance to neoadjuvant chemotherapy in LARC. Together, our work revealed an important role of CDK4/6 pathway in LARC patients with neoadjuvant chemotherapy, suggesting that targeting CDK4/6 could provide a potentially effective treatment strategy for LARC.
2024-02-26 | GSE205035 | GEO