Biology subjects

Dacus, D.

Publications and source records attributed to Dacus, D..

4 recordsLinked to original sources

bioRxiv2026

Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor

Therapeutic inhibition of the RAS/MAPK cascade, an oncogenic driver in over one-third of human cancers, has been limited by a core trade-off: effective pathway blockade in tumors versus dose-limiting toxicity in normal tissues. Although Type 1.5 RAF inhibitors successfully mitigated this trade-off in BRAF-monomer-driven tumors, an equivalent strategy has been lacking for RAF-dimer-driven cancers, including those with RAS mutations. Here, we characterize ELV-3111, a next-generation, potent, and selective Type 1 RAF inhibitor that overcomes this limitation via a distinct mechanism of action. ELV-3111 induces paradoxical MAPK hyperactivation in normal tissues by binding RAF and promoting the active conformation (priming) followed by rapid dissociation (fast off-rate), a biochemical feature that spares RAS-mutant tumors, where RAF is already primed. In these and other RAF dimer-driven tumor models, ELV-3111 achieves potent and selective MAPK and growth suppression. When combined with a MEK inhibitor, ELV-3111 enables complementary pharmacology: additive inhibition in tumors and compensatory effects in normal tissues. The combination produced durable regressions across RAS-mutant and BRAF-mutant models, including a RAS-mutant model refractory to current therapies, while maintaining favorable tolerability. Thus, we uncover a generalizable mechanism that enables Type 1 RAF inhibitor plus MEK inhibitor combinations to achieve tumor-selective MAPK suppression, with the potential to inform targeted therapy design.

cancer biology↗

bioRxiv2024

Cutaneous human papillomavirus E6 impairs the cGAS-STING pathway

Beta genus human papillomaviruses ({beta}-HPVs) are ubiquitous double stranded DNA (dsDNA) viruses that may promote skin cancers by destabilizing the host genome. Supporting this, expression of the E6 gene from a {beta}-HPV ({beta}-HPV 8 E6) results in increased micronuclei that should induce an innate immune response that eliminates these cells. Yet, {beta}-HPV 8 E6 promotes rather than restricts proliferation. We hypothesize that {beta}-HPV 8 E6 accomplishes this by attenuating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, an innate immune pathway that becomes activated in response to cytosolic micronuclear dsDNA. Here, we show that in response to stimulation by transfection of pLVX-GFP plasmid, {beta}-HPV 8 E6 reduced the magnitude and intensity of cGAS-STING pathway activation in immunoblot experiments. These data also demonstrate that impairment of the cGAS-STING pathway is strongest downstream of STING phosphorylation. Further, RNA-sequencing suggests that {beta}-HPV 8 E6 downregulates other innate immune pathways. We also show that cGAS is recruited to micronuclei induced by {beta}-HPV 8 E6. These data suggest a mechanism by which {beta}-HPV 8 E6 facilitates proliferation of cells destabilized by micronuclei and support the hypothesis that the prevalence of {beta}-HPV infections is in part due to the impairment of the cGAS-STING innate immune response.

cancer biology↗

bioRxiv2022

Beta HPV8 E6 Induces Micronuclei Formation and Promotes Chromothripsis

Cutaneous beta genus human papillomaviruses ({beta}-HPV) are suspected to promote the development of non-melanoma skin cancer (NMSC) by destabilizing the host genome. Multiple studies have established the genome destabilizing capacities of {beta}-HPV proteins E6 and E7 as a co-factor with UV. However, the E6 protein from {beta}-HPV8 (HPV8 E6) induces tumors in mice without UV exposure. Here, we examined a UV-independent mechanism of HPV8 E6-induced genome destabilization. We showed that HPV8 E6 reduced the abundance of anaphase bridge resolving helicase, Bloom syndrome protein (BLM). The diminished BLM was associated with increased segregation errors and micronuclei. These HPV8 E6-induced micronuclei had disordered micronuclear envelopes yet retained replication and transcription competence. HPV8 E6 decreased antiproliferative responses to micronuclei and time-lapse imaging revealed HPV8 E6 promoted cells with micronuclei to complete mitosis. Finally, whole genome sequencing revealed that HPV8 E6 induced chromothripsis in 9 chromosomes. These data provide insight into mechanisms by which HPV8 E6-induces genome instability independent of UV exposure. ImportanceSome beta genus human papillomaviruses ({beta}-HPVs) may promote skin carcinogenesis by inducing mutations in the host genome. Supporting this, the E6 protein from {beta}-HPV8 (8E6) promotes skin cancer in mice with or without UV exposure. Many mechanisms by which 8E6 increases mutations caused by UV have been elucidated, but less is known about how 8E6 induces mutations without UV. We address that knowledge gap by showing 8E6 causes mutations stemming from mitotic errors. Specifically, 8E6 reduces the abundance of BLM, a helicase that resolves and prevents anaphase bridges. This hinders anaphase bridge resolution and increases their frequency. 8E6 makes the micronuclei that can result from anaphase bridges more common. These micronuclei often have disrupted envelopes yet retain localization of nuclear-trafficked proteins. 8E6 promotes the growth of cells with micronuclei and causes chromothripsis, a mutagenic process where hundreds to thousands of mutations occur in a chromosome.

cancer biology↗

bioRxiv2019

β-HPV 8E6 Dysregulates the Hippo Signaling Pathway and Induces Aneuploidy

Beta genus human papillomaviruses ({beta}-HPVs) are associated with cutaneous squamous cell carcinomas (cSCCs) in a subset of immunocompromised patients. Although {beta}-HPVs are not necessary for tumor maintenance, they are hypothesized to destabilize the genome in the early stages of cancer development. Supporting this idea, {beta}-HPVs 8E6 protein attenuates p53 accumulation after failed cytokinesis. This paper identifies the mechanism of this abatement. We show {beta}-HPV 8E6 dysregulates the Hippo signaling pathway (HP). It increases pro-proliferative gene expression, enhances TEAD activity and promotes cell growth. {beta}-HPV 8E6 also reduces LATS activation and p53-mediated apoptosis following unsuccessful division of mitotic cells. These phenotypes are dependent on {beta}-HPV 8E6 binding and destabilizing a cellular histone acetyltransferase, p300. Despite circumventing apoptosis, {beta}-HPV 8E6 caused increased senescence after unsuccessful cytokinesis. We linked this lack of growth to the viral proteins inability to prevent cytoplasmic sequestration of the HP transcription factor, YAP. We also show that increased telomerase reverse transcriptase activity (a common alteration in cSCCs) acts synergistically with {beta}-HPV 8E6 to promote cellular proliferation after abortive cytokinesis. While {beta}-HPV 8E6 promoted aneuploidy on its own, this genome destabilization is amplified in cells that do not divide after mitosis. Although our group and others have previously described inhibition of DNA repair, to the best of our knowledge this marks the first time that a {beta}-HPV protein has been connected to chromosome level changes in the cellular genome. This represents a substantial escalation in the known genome destabilizing properties likely to occur during a {beta}-HPV infection.\n\nIMPORTANCEThere is mounting evidence that {beta}-HPVs contribute to cSCCs development in immunocompromised populations. They may also augment UVs mutagenic potential, increasing cancer risk in the general population. We demonstrate that {beta}-HPV 8E6 dysregulates the Hippo signaling pathway (HP). HP regulates cell growth and apoptosis in response to a myriad of stimuli, including failed cytokinesis. {beta}-HPV 8E6 attenuates phosphorylation of the HP kinase, LATS, decreasing some but not all downstream signaling events. This allows binucleated cells to avoid apoptosis, however they succumb to senescence. We show that {beta}-HPV 8E6 synergizes with a common cSCC mutation (telomerase activation) to avoid both apoptosis and senescence. We did not find any telomerase immortalized {beta}-HPV 8E6 expressing cells that were not aneuploid after aberrant cytokinesis. This represents a substantial escalation in {beta}-HPV E6s known mutagenic potential.

cancer biology↗