Harnessing the TAF1 Acetyltransferase for Targeted Acetylation of the Tumor Suppressor p53.

Pharmacological reactivation of the tumor suppressor p53 remains a key challenge for the treatment of cancer. Acetylation Targeting Chimera (AceTAC), a novel technology is previously reported that hijacks lysine acetyltransferases p300/CBP to acetylate the p53Y220C mutant. However, p300/CBP are the only acetyltransferases harnessed for AceTAC development to date.

Design, Synthesis, and Evaluation of p53Y220C Acetylation Targeting Chimeras (AceTACs).

The well-known tumor suppressor p53 is mutated in approximately half of all cancers. The Y220C mutation is one of the major p53 hotspot mutations. Several small-molecule stabilizers of p53Y220C have been developed.

Differential histone acetylation and super-enhancer regulation underlie melanoma cell dedifferentiation.

Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low versus high risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively.

Molecular mechanisms in colitis-associated colorectal cancer.

Sustained chronic inflammation of the large intestine leads to tissue damage and repair, which is associated with an increased incidence of colitis-associated colorectal cancer (CAC). The genetic makeup of CAC is somewhat similar to sporadic colorectal carcinoma (sCRC), but there are differences in the sequence and timing of alterations in the carcinogenesis process. Several models have been developed to explain the development of CAC, particularly the "field cancerization" model, which proposes that chronic inflammation accelerates mutagenesis and selects for the clonal expansion of phenotypically normal, pro-tumorigenic cells.

Etiology of super-enhancer reprogramming and activation in cancer.

Super-enhancers are large, densely concentrated swaths of enhancers that regulate genes critical for cell identity. Tumorigenesis is accompanied by changes in the super-enhancer landscape. These aberrant super-enhancers commonly form to activate proto-oncogenes, or other genes upon which cancer cells depend, that initiate tumorigenesis, promote tumor proliferation, and increase the fitness of cancer cells to survive in the tumor microenvironment.

AKT activation because of PTEN loss upregulates xCT via GSK3β/NRF2, leading to inhibition of ferroptosis in PTEN-mutant tumor cells.

Here, we show that the tumor suppressor phosphatase and tensin homolog deleted from chromosome 10 (PTEN) sensitizes cells to ferroptosis, an iron-dependent form of cell death, by restraining the expression and activity of the cystine/glutamate antiporter system X (xCT). Loss of PTEN activates AKT kinase to inhibit GSK3β, increasing NF-E2 p45-related factor 2 (NRF2) along with transcription of one of its known target genes encoding xCT. Elevated xCT in Pten-null mouse embryonic fibroblasts increases the flux of cystine transport and synthesis of glutathione, which enhances the steady-state levels of these metabolites.

B7-H3 drives immunosuppression and Co-targeting with CD47 is a new therapeutic strategy in β-catenin activated melanomas.

In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T-cell non-inflamed tumors (cold tumors) are associated with tumor cell-intrinsic Wnt/β-catenin activation, and are typically resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the 'cold tumor' phenotype and identifying new effective immunotherapies are challenges.

A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma.

Tumors exhibit enhancer reprogramming compared to normal tissue. The etiology is largely attributed to cell-intrinsic genomic alterations. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon, we find divergent epigenetic landscapes between CRC tumors and cell lines.

Novel Allosteric Inhibitor-Derived AKT Proteolysis Targeting Chimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells.

AKT is an important target for cancer therapeutics. Significant advancements have been made in developing ATP-competitive and allosteric AKT inhibitors. Recently, several AKT proteolysis targeting chimeras (PROTACs) derived from ATP-competitive AKT inhibitors have been reported, including MS21.

Inpatient Administration of Alpha-1-Adrenergic Receptor Blocking Agents Reduces Mortality in Male COVID-19 Patients.

Apha-1-adrenergic receptor antagonists (α-blockers) can suppress pro-inflammatory cytokines, thereby potentially improving outcomes among patients with COVID-19. Accordingly, we evaluated the association between α-blocker exposure (before or during hospitalization) and COVID-19 in-hospital mortality. We identified 2,627 men aged 45 or older who were admitted to Mount Sinai hospitals with COVID-19 between February 24 and May 31, 2020, in New York.

Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders.

The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure-activity relationship (SAR) results have been reported.

Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma.

Background And Aims: The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity.

PTEN interacts with the transcription machinery on chromatin and regulates RNA polymerase II-mediated transcription.

Regulation of RNA polymerase II (RNAPII)-mediated transcription controls cellular phenotypes such as cancer. Phosphatase and tensin homologue deleted on chromosome ten (PTEN), one of the most commonly altered tumor suppressors in cancer, affects transcription via its role in antagonizing the PI3K/AKT signaling pathway. Using co-immunoprecipitations and proximal ligation assays we provide evidence that PTEN interacts with AFF4, RNAPII, CDK9, cyclin T1, XPB and CDK7.

Molecular Pathways: Targeting the PI3K Pathway in Cancer-BET Inhibitors to the Rescue.

The PI3K signaling pathway is a complex and tightly regulated network that is critical for many physiologic processes, such as cell growth, proliferation, metabolism, and survival. Aberrant activation of this pathway can occur through mutation of almost any of its major nodes and has been implicated in a number of human diseases, including cancer. The high frequency of mutations in this pathway in multiple types of cancer has led to the development of small-molecule inhibitors of PI3K, several of which are currently in clinical trials.

Molecular pathways: intercellular PTEN and the potential of PTEN restoration therapy.

Phosphatase and Tensin homolog deleted on chromosome Ten (PTEN) acts as a tumor suppressor through both PI3K-dependent and -independent mechanisms. Reduced PTEN activity has been shown to affect not only tumor cell proliferation and survival but also the microenvironmental context in which nascent tumors develop. As a result of the multifaceted tumor-suppressive roles of PTEN, tumors evolve by selecting for clones in which PTEN activity is lost.

Metformin and erlotinib synergize to inhibit basal breast cancer.

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth.

PTEN function: the long and the short of it.

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a phosphatase that is frequently altered in cancer. PTEN has phosphatase-dependent and -independent roles, and genetic alterations in PTEN lead to deregulation of protein synthesis, the cell cycle, migration, growth, DNA repair, and survival signaling. PTEN localization, stability, conformation, and phosphatase activity are controlled by an array of protein-protein interactions and post-translational modifications.

Alterations of EGFR, p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of human mammary epithelial cells.

Breast cancer can be classified into different molecular subtypes with varying clinical and pathological characteristics. The basal-like breast cancer subtype represents one of the most aggressive and lethal types of breast cancer, and due to poor mechanistic understanding, it lacks targeted therapy. Many basal-like breast cancer patient samples display alterations of established drivers of cancer development, including elevated expression of EGFR, p53 inactivating mutations and loss of expression of the tumor suppressor PTEN; however, their contribution to human basal-like breast cancer pathogenesis remains ill-defined.

Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer.

While the small GTPase Rac1 and its effectors are well-established mediators of mitogenic and motile signaling by tyrosine kinase receptors and have been implicated in breast tumorigenesis, little is known regarding the exchange factors (Rac-GEFs) that mediate ErbB receptor responses. Here, we identify the PIP(3)-Gβγ-dependent Rac-GEF P-Rex1 as an essential mediator of Rac1 activation, motility, cell growth, and tumorigenesis driven by ErbB receptors in breast cancer cells. Notably, activation of P-Rex1 in breast cancer cells requires the convergence of inputs from ErbB receptors and a Gβγ- and PI3Kγ-dependent pathway.