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Introduction The introduction of proapoptotic pharmacological agents such as the antiapoptotic protein Bcl-2 inhibitor VEN has revolutionized the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Although [...], Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching" interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak doubleknockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.

Introduction Amplified-HER2 breast cancer is an aggressive disease that until recently had the worst overall survival prognosis among breast cancer subtypes (1, 2). The clinical implementation of HER2-targeted therapies, including [...], The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in [HER2.sup.+] disease, examining the relationship between HER2 expression and MYC phosphorylation in [HER2.sup.+] patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC; NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC; NeuNT tumors match existing subtypes of amplified-HER2, estrogen receptor-negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR-targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers.

Introduction The complete molecular and functional characterization of key oncogenic signaling pathways in human cancer has allowed for a greater understanding of mechanisms involved in signal transduction and has laid [...], EGFR activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms, including activation of AKT signaling. Though much is known about the specific molecular lesions conferring resistance to anti-EGFR-based therapies, additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. We identified a transcriptional network involving the tumor suppressors Kruppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that negatively regulates activated EGFR signaling in both cell culture and in vivo models. Furthermore, the use of the FDA-approved drug trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models of lung adenocarcinoma. Combined, these findings define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs as capable of restoring chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma.

The U.S. Dietary Guidelines lack oversight and accountability. The result: Guidelines that reflect food industry interests instead of modern science. This deleterious guidance goes on to govern federally-subsidized food assistance programs and to influence dietary choices throughout the private sector and private life. Ultimately, the Guidelines significantly contribute to the endemic chronic disease they seek to address. The Guidelines Advisory Committee is notoriously rife with conflicts of interest, and thus most Guidelines scholarship has focused on reforming the Committee. But the 2015 and 2020 Guidelines show that these reforms are insufficient and agency-level change is necessary. In 2015, the Committee made several controversial recommendations related to red meat, ultraprocessed foods, sodium, and sustainability. Due to industry backlash, only the sodium recommendation survived in the final Guidelines published by the Secretaries of the U.S. Departments of Agriculture (USDA) and Health and Human Services (HHS). In 2020, the Secretaries, for the first time, predetermined a list of eighty topics that the Committee may consider. Absent from this list are the most contentious topics from previous years. There is little recourse because the Guidelines are not considered an agency action subject to the Administrative Procedure Act (APA), despite their vast impact on food assistance programs, healthcare practices, tort law, and more. This Note proposes two ways to bring the Guidelines within the APA's coverage. The first is a litigation strategy, arguing that the D.C. District Court relied on erroneous reasoning when it held that the Guidelines are not an agency action subject to the APA. Second, this Note describes some ways that Congress could amend the Nutrition Act, the statute governing the Guidelines. Applying the APA to the Guidelines would allow for public participation and public challenge, greater transparency, and greater efficiency across agencies. Evidence-based Guidelines would improve overall health, reduce healthcare costs, and ensure that food assistance beneficiaries can access healthy foods. A robust set of Guidelines would improve public confidence in the recommendations and enable further food law reforms, such as amending the Farm Bill, that would make it easier for people to make healthy choices. [ABSTRACT FROM AUTHOR]