Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors.

Acting as molecular switches, all three members of the Guanosine triphosphate (GTP)-ase-family, Ras-related C3 botulinum toxin substrate (RAC), Rho, and Cdc42 contribute to various processes of oncogenic transformations in several solid tumors. We have reviewed the distribution of patterns regarding the frequency of Ras-related C3 botulinum toxin substrate 1 (RAC1)-alteration(s) and their modes of actions in various cancers. The RAC1 hyperactivation/copy-number gain is one of the frequently observed features in various solid tumors. We argued that RAC1 plays a critical role in the progression of tumors and the development of resistance to various therapeutic modalities applied in the clinic. With this perspective, here we interrogated multiple functions of RAC1 in solid tumors pertaining to the progression of tumors and the development of resistance with a special emphasis on different tumor cell phenotypes, including the inhibition of apoptosis and increase in the proliferation, epithelial-to-mesenchymal transition (EMT), stemness, pro-angiogenic, and metastatic phenotypes. Our review focuses on the role of RAC1 in adult solid-tumors and summarizes the contextual mechanisms of RAC1 involvement in the development of resistance to cancer therapies.

The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies.

Human Epidermal Growth Factor Receptor 2-positive breast cancer (HER2+ BC) is defined by increased amplification of the ERBB2/neu oncogene and/or overexpression of its associated HER2 transmembrane receptor protein. HER2+ BC represents approximately 15-20% of breast cancer, and it is independently associated with a higher grade, more aggressive phenotype, and worse prognosis. With the advent of trastuzumab, the prognostic landscape for HER2+ BC patients has considerably improved. However, both de novo and acquired resistance to trastuzumab remain a significant obstacle for many patients, requiring novel therapies for further clinical benefit. Over the last two decades, there has been extraordinary progress in the development of HER2+ BC treatment regimens, with extensions into HER2-amplified gastroesophageal junction cancer via the NCI-MATCH precision medicine trial program (NCT02465060). Trastuzumab, pertuzumab, T-DM1, and lapatinib are commonly recommended as a single agent (along with chemotherapy) or in combinations of anti-HER2 agents in neoadjuvant, adjuvant and metastatic settings according to National Comprehensive Cancer Network (NCCN) guidelines. Currently, the combination of trastuzumab, pertuzumab, and taxane chemotherapy are first-line for HER2+/HR- metastatic breast cancer with potential breakthrough therapies such as trastuzumab-deruxtecan (DS-8201a), margetuximab and tucatinib (ONT-380) on the horizon. Furthermore, recent clinical trials have demonstrated the potential utility of hormone receptor status, PAM-50 luminal intrinsic subtype, PD-L1, and TIL as predictive biomarkers for response to HER2+ therapies. We briefly introduce the origin of HER2, the invention of trastuzumab, and the classification of HER2+ BC. Each HER2-targeted therapy is then presented by indication, mechanism of action, and relevant clinical trials with subsequent elaboration and contextualization within clinical settings with an epilogue of potential future biomarkers for clinical use in HER2+ BC. We summarize the most significant and updated research in clinical practice relevant to HER2+ BC management and highlight the clinical status of upcoming anti-HER2 agents as well as immunotherapy drugs in combination with anti-HER2 agents.

Cambiarenes: Single-Step Synthesis and Selective Zwitterion Binding of a Clip-Shaped Macrocycle with a Redox-Active Core.

A novel macrocyclic host molecule was synthesized that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, it is redox-active. Host-guest binding involving the clip-shaped cavity indicates selective binding of pyridine N-oxides based on the electron density of and steric bulk around the anionic oxygen.

ER+ metastatic breast cancer: past, present, and a prescription for an apoptosis-targeted future.

The importance and role of the estrogen receptor (ER) pathway have been well-recognized in both breast cancer development and progression. The treatment of choice in women with estrogen receptor-positive metastatic breast cancer (ER+ mBC) is classically divided into a variety of endocrine therapies, with three of the most common being: selective estrogen receptor modulators (SERM), aromatase inhibitors (AI), and selective estrogen receptor degraders (SERD). However, resistance develops in 30-50% of patients treated with these endocrine therapies due to a sophisticated and at times redundant interference at the molecular level between the ER, growth factors, and downstream cell-signaling pathways. Tumor response is heightened with adjunctive therapy that includes an mTORC1 inhibitor (everolimus), CDK4/6 inhibitors (palbociclib/ribociclib/abemaciclib), and an α isoform-specific PI3K inhibitor (alpelisib). Each of these inhibitors elicits potent anti-proliferative benefits; however, they fail to induce tumor cell death. Consequently, disease progression almost invariably occurs. Evasion of apoptosis is a hallmark of cancer. The p53 and BCL2 represent two important nodes of the apoptosis signaling pathway. Venetoclax, a potent and selective BCL2 inhibitor, synergizes with hormonal therapy in ER+ breast cancer models and is active in clinical trials. Similarly, an MDM2 inhibitor, AMG-232, which induces p53 is active in early clinical trials of both liquid and advanced solid tumor patients. In our ER+ BC cohort (Avera Cancer Institute, Sioux Falls, SD), we observed more than 70% of wild type TP53 and over 10% amplification of MDM2 and MDM4 as comparable with the TCGA data set. We summarized current treatment options, the molecular mechanisms that predispose to endocrine resistance, and a future pro-apoptotic treatment strategy for ER+ mBC patients. Our review presents critical analyses of the therapeutic options for the clinical management of ER+ Metastatic Breast Cancer in the light of a hypothesis targeting the induction of apoptosis in p53 wild type tumors. We reviewed not only the FDA approved current treatment approaches but also presented a discourse addressing the possibilities for novel combination strategy that can induce tumor cell apoptosis, a critical cellular mechanism delaying/denying tumor progression. Our review is unique as it presents patient data in support of our hypothesis.