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Genome-Wide CRISPR-Cas9 screening identifies BRAF inhibitor as a sensitizer of dasatinib in treating T-acute lymphoblastic leukemia

ABSTRACT: Genome-Wide CRISPR-Cas9 screening identifies BRAF inhibitor as a sensitizer of dasatinib in treating T-acute lymphoblastic leukemia

PROVIDER: PRJNA902286 | ENA |

REPOSITORIES: ENA

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Project description:Despite high initial activity, resistance to combination BRAF/MEK inhibitor (BRAFi/MEKi) therapy arises in virtually all patients with BRAFV600E/K melanoma. There remains a critical unmet need to identify strategies to overcome acquired BRAFi/MEKi resistance. To better personalize therapy in cancer patients and address therapy relapse, umbrella trials have commenced whereby genomic sequencing of a panel of potentially actionable targets guide therapy selection for patients. However, the superior efficacy of such approaches remains to be seen. We here test the robustness of the umbrella trial rationale by analyzing relationships between genomic status of a gene and the downstream consequences at the protein level of related pathways, and find poor relationships between mutations, copy number amplification, and protein expression and activation. To profile candidate therapeutic strategies that may offer clinical benefit in the context of acquired BRAFi/MEKi resistance, we utilized a repository of patient-derived xenograft models from heavily pretreated patients with resistance to BRAFi/MEKi and/or immunotherapy (R-PDX). With these R-PDXs, we executed in vivo compound repurposing screens using 11 FDA-approved agents from an NCI-portfolio with pan-RTK, non-RTK and/or PI3K-mTOR specificity. We identify dasatinib as capable of restoring sensitivity to BRAFi/MEKi in ~70% of R-PDX models tested. Elevated baseline protein expression of canonical drivers of therapy resistance (e.g., AXL, YAP, HSP70, phospho-AKT) predicts BRAFi/MEKi plus dasatinib treatment sensitivity. We therefore propose that dasatinib plus BRAFi/MEKi combination therapy may restore antitumor efficacy in patients that have relapsed to standard-of-care therapy by broadly targeting proteins critical in melanoma therapy escape. Further, we submit that this experimental PDX paradigm could potentially improve preclinical evaluation of therapeutic modalities and augment our ability to identify biomarker-defined patient subsets that may respond to a given clinical trial. Furthermore, the aged patient population has suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterize vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in 18-month-old mice and interrogate protection. Aged mice have altered cellular responses, including decreased IFNγ secretion and increased TNFα secretion as compared to young mice. Aged mice had significantly decreased binding and neutralizing antibodies in their serum compared to their young counterparts. Co-immunization with the plasmid-encoded molecular adjuvant adenosine deaminase-1 (pADA) enhanced cellular responses and expanded the breadth of humoral responses in aged mice. pADA co-delivery also altered the gene expression profiles of lymph node lymphocytes in aged animals. Upon challenge pADA co-immunization modestly decreased age-associated morbidity and mortality in ACE2 transgenic and mouse-adapted SARS-CoV-2 challenge models. These data support the use of aged mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 and provide further support of the use of adenosine deaminase as a molecular adjuvant.

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Genome-Wide CRISPR-Cas9 screening identifies BRAF inhibitor as a sensitizer of dasatinib in treating T-acute lymphoblastic leukemia

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