Biology subjects

Fruman, D. A.

Publications and source records attributed to Fruman, D. A..

3 recordsLinked to original sources

bioRxiv2024

Cholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer deaths due to its molecular heterogeneity, high recurrence rate and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. We performed a genome-wide CRISPR/Cas9 screen with PI3K and AKT inhibitors to find targetable synthetic lethalities in TNBC. We identified cholesterol homeostasis as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro, in mouse TNBC xenografts and in patient-derived, estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single agent or combination treatment with AKT inhibitor and pitavastatin. This was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. Our work motivates combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC.

cancer biology↗

bioRxiv2022

The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase

IQGAP1 is a multi-domain cancer-associated protein that serves as a scaffold protein for multiple signaling pathways. Numerous binding partners have been found for the calponin homology, IQ and GAP-related domains in IQGAP1. Identification of a binding partner for its WW domain has proven elusive, however, even though a cell-penetrating peptide derived from this domain has marked anti-tumor activity. Here, using in vitro binding assays with human proteins and co-precipitation from human cells, we show that the WW domain of human IQGAP1 binds directly to the p110 catalytic subunit of phosphoinositide 3-kinase (PI3K). In contrast, the WW domain does not bind to ERK1/2, MEK1/2, or the p85 regulatory subunit of PI3K when p85 is expressed alone. However, the WW domain is able to bind to the p110/p85 heterodimer when both subunits are co-expressed, as well as to the mutationally activated p110/p65 heterodimer. We present a model of the structure of the IQGAP1 WW domain, and experimentally identify key residues in the hydrophobic core and beta strands of the WW domain that are required for binding to p110. These findings contribute to a more precise understanding of IQGAP1-mediated scaffolding, and of how IQGAP1-derived therapeutic peptides might inhibit tumorigenesis.

biochemistry↗

bioRxiv2020

Measuring effects of trainee professional development on research productivity: A cross-institutional meta-analysis

PhD-trained scientists are essential contributors to the workforce in diverse employment sectors that include academia, industry, government, and non-profit organizations. Hence, best practices for training the future biomedical workforce are of national concern. Complementing coursework and laboratory research training, many institutions now offer professional training that enables career exploration and develops a broad set of skills critical to various career paths. The National Institutes of Health funded academic institutions to design innovative programming to enable this professional development through a mechanism known as Broadening Experiences in Scientific Training (BEST). Programming at the BEST awardee institutions included career panels, skill-building workshops, job-searching workshops, site visits, and internships. An initial concern was since doctoral training is lengthy and requires focused attention on dissertation research, having students participate in additional complementary training activities might lengthen time to degree and hamper student research productivity. To address this concern, using time to degree and publication records as measures of efficiency and productivity, metrics were analyzed from ten BEST awardee institutions. Comparing doctoral students who participated to those who did not, results revealed that across these diverse academic institutions, there were no differences in time to degree or manuscript output. Furthermore, a few institutions even demonstrated a positive correlation between participation in career and professional development activities and productivity. Our findings suggest that doctoral students should be encouraged to participate in career and professional development opportunities to ensure their preparedness for a variety of diverse and important careers in the workforce. Significance StatementOur study is unique in that it compiled doctoral degree durations at ten different universities, recorded individual participation in career and professional development activities in terms of dosage, and tracked individual engagement in real-time rather than relying on surveys sent to trainees after graduation. Participation in career and professional development activities, including internships, did not decrease efficiency or productivity. Our findings suggest that doctoral students should be encouraged to participate in career and professional development opportunities to ensure their preparedness for a variety of diverse and important careers in the workforce.

scientific communication and education↗