The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers.

Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors.

Chromatin-bound RB targets promoters, enhancers, and CTCF-bound loci and is redistributed by cell-cycle progression.

The interaction of RB with chromatin is key to understanding its molecular functions. Here, for first time, we identify the full spectrum of chromatin-bound RB. Rather than exclusively binding promoters, as is often described, RB targets three fundamentally different types of loci (promoters, enhancers, and insulators), which are largely distinguishable by the mutually exclusive presence of E2F1, c-Jun, and CTCF.

KRAS-independent feedback activation of wild-type RAS constrains KRAS inhibitor efficacy.

Although KRAS has long been considered undruggable, direct KRAS inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear.

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment.

We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine.

Clinical Acquired Resistance to KRAS Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation.

Mutant-selective KRAS inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in -mutant cancers, including non-small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRAS inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (), all of which converge to reactivate RAS-MAPK signaling.

Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRAS Inhibition.

Purpose: Although represents the most commonly mutated oncogene, it has long been considered an "undruggable" target. Novel covalent inhibitors selective for the KRAS mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS-MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance.

WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop.

β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex.

Therapeutic strategies to target RAS-mutant cancers.

RAS genes are the most commonly mutated oncogenes in cancer, but effective therapeutic strategies to target RAS-mutant cancers have proved elusive. A key aspect of this challenge is the fact that direct inhibition of RAS proteins has proved difficult, leading researchers to test numerous alternative strategies aimed at exploiting RAS-related vulnerabilities or targeting RAS effectors. In the past few years, we have witnessed renewed efforts to target RAS directly, with several promising strategies being tested in clinical trials at different stages of completion.

The Importance of Self-Efficacy in Parental Emergency Preparedness: A Moderated Mediation Model.

Objective: Disasters occur without warning and can have devastating consequences. Emergency preparedness can reduce negative effects. It is especially important that parents prepare, as children are particularly vulnerable after disasters.

A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.

Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K.

ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma.

Unlabelled: Recently, we identified that PREX1 overexpression is critical for metastatic but not tumorigenic growth in a mouse model of NRAS-driven melanoma. In addition, a PREX1 gene signature correlated with and was dependent on ERK MAPK activation in human melanoma cell lines. In the current study, the underlying mechanism of PREX1 overexpression in human melanoma was assessed.

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.

The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer.

Targeting -mutant cancers: is ERK the key?

The three genes comprise the most frequently mutated oncogene family in cancer. With significant and compelling evidence that continued function of mutant is required for tumor maintenance, it is widely accepted that effective anti-RAS therapy will have a significant impact on cancer growth and patient survival. However, despite more than three decades of intense research and pharmaceutical industry efforts, a clinically effective anti-RAS drug has yet to be developed.

Extracellular signal-regulated kinase (ERK) phosphorylates histone deacetylase 6 (HDAC6) at serine 1035 to stimulate cell migration.

Histone deacetylase 6 (HDAC6) is well known for its ability to promote cell migration through deacetylation of its cytoplasmic substrates such as α-tubulin. However, how HDAC6 itself is regulated to control cell motility remains elusive. Previous studies have shown that one third of extracellular signal-regulated kinase (ERK) is associated with the microtubule cytoskeleton in cells.

GSK-3α promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-κB.

Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin. The NF-κB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently, TGF-β-activated kinase 1 (TAK1), an upstream regulator of IκB kinase (IKK), which controls canonical NF-κB signaling, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS-mutant colorectal cancer cell growth and survival.

CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells.

Previous studies have identified interleukin 6 (IL-6) as an important cytokine with prognostic significance in ovarian cancer. Activation of the IL-6-Stat3 pathway contributes to tumor cell growth, survival and drug resistance in several cancers, including ovarian cancer. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of CDDO-Me, a synthetic triterpenoid, to inhibit IL-6 secretion, Stat3 phosphorylation, Stat3 nuclear translocation and paclitaxel sensitivity in several cell line model systems.

Use of in situ isopropoxide protection in the metal-halogen exchange of arylboronates.

Isopropoxide protection of arylboronates allowed their use in metal-halogen exchange reactions. The isopropoxide-protected borate species were obtained from a boronate or in situ from dibromoarenes. meta- and para-dibromoarenes were converted via these intermediates into functionalized arylboronates in a one-pot manner.