Biology subjects

Floros, K. V.

Publications and source records attributed to Floros, K. V..

3 recordsLinked to original sources

bioRxiv2026

Daraxonrasib (RMC-6236) is an effective targeted therapy for RAS-mutant neuroblastoma

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Relapsed or refractory (R/R) high-risk (HR) NB tumors continue to exhibit poor outcomes despite intensive and protractive multimodal therapy. Activating mutations in the RAS- mitogen-activated protein kinase (MAPK) pathway are frequently observed in R/R HRNB. The early promise of ALK inhibitors to treat ALK-mutant NB underscores the ability of appropriate targeted therapies to improve outcomes for HRNB patients. While MAPK pathway activation is prominent in HRNB, FDA-approved MEK inhibitors and KRAS G12C inhibitors have failed to demonstrate significant preclinical single-agent activity. Daraxonrasib (RMC-6236), a potent and selective RAS(ON) inhibitor, has demonstrated activity in both preclinical models and early phase clinical trials of RAS-mutant adult cancers. A subset of R/R HRNB tumors is noteworthy for containing diverse RAS-mutations, providing rationale for RMC-6236 investigation. In this study, we evaluated the therapeutic efficacy and oncogenic signaling modulation of RMC-6236 across NB models harboring RAS pathway activation. RMC-6236 as a single-agent treatment led to a significant decrease in cell viability, suppression of downstream MAPK signaling, upregulation of the MAPK pathway effector protein BIM, and increased cell death in RAS-mutant NB models as well as in NF1-mutant NB models. In vivo studies evidenced that RMC-6236 had on-target activity that significantly reduced tumor growth and extended survival in RAS-mutant HRNB mouse models. Furthermore, RMC-6236-induced both BCL-2 and BIM upregulation and enhancement of BIM:BCL-2 complexes in RAS-mutant NB. As such, the BCL-2 inhibitor venetoclax further enhanced RMC-6236-mediated killing by disrupting RMC-6236 enhanced BIM:BCL-2 complexes. These findings demonstrate that RMC-6236 is a rationale targeted therapy for RAS-mutant NB, a subset of NB that is progressively understood as conferring particularly poor outcomes. RMC-6236 is a clinically relevant drug that can successfully target the MAPK pathway in these cancers. This study supports expanded clinical testing of this novel therapy to this important subset of neuroblastoma.

cancer biology↗

bioRxiv2024

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

cancer biology↗

bioRxiv2022

Genomic screening reveals UBA1 as a potent and druggable target in c-MYC-high TNBC models

Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer-related deaths, despite accounting for only 10%-15% of total breast cancer cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). Targeting UBA1 with the first in-class UBA1 inhibitor TAK-243 induced unresolvable ER-stress and activating transcription factor 4 (ATF4)-mediated upregulation of pro-apoptotic NOXA, leading to cell death. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. In an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. Lastly, c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. We posit UBA1 is an important new target in TNBC expressing high levels of c-MYC. SignificanceGenomic screening of TNBC cell lines revealed broad sensitivity to depletion of the E1 ubiquitin enzyme, UBA1. Disrupting UBA1 with the first in-class inhibitor TAK-243 in TNBC models induces ER-stress through an ATF4-NOXA axis that is dependent on c-MYC, leading to apoptosis, in vitro and in vivo, primary tumor growth inhibition and metastatic inhibition.

cancer biology↗