Biology subjects

Fingerman, D.

Publications and source records attributed to Fingerman, D..

3 recordsLinked to original sources

bioRxiv2023

Dasatinib Resensitizes MAPK Inhibitor Efficacy in Standard-of-Care Relapsed Melanomas

Resistance to combination BRAF/MEK inhibitor (BRAFi/MEKi) therapy arises in nearly every patient with BRAFV600E/K melanoma, despite promising initial responses. Achieving cures in this expanding BRAFi/MEKi-resistant cohort represents one of the greatest challenges to the field; few experience additional durable benefit from immunotherapy and no alternative therapies exist. To better personalize therapy in cancer patients to address therapy relapse, umbrella trials have been initiated 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 pathway, which find poor relationships between mutations, copy number amplification, and protein level. To profile candidate therapeutic strategies that may offer clinical benefit in the context of acquired BRAFi/MEKi resistance, we established 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 BRAFi/MEKi antitumor efficacy in [~]70% of R-PDX tested. A systems-biology analysis indicates elevated baseline protein expression of canonical drivers of therapy resistance (e.g., AXL, YAP, HSP70, phospho-AKT) as predictive of MAPKi/dasatinib sensitivity. We therefore propose that dasatinib-based MAPKi 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. SINGLE SENTENCE SUMMARYBroad target inhibition effective as a salvage strategy in BRAF/MEK inhibitor-acquired resistance PDX

cancer biology↗

bioRxiv2022

Metastatic potential in clonal melanoma cells is driven by a rare, early-invading subpopulation

Metastasis occurs when tumor cells leave the primary tumor site and disseminate to distal organs. Even though most cells remain in the primary tumor, the circumstances by which a small fraction of them disseminate remain unclear. Here, we show that a rare, highly invasive subpopulation of melanoma cells can be detected within clonal cell lines due to non-genetic fluctuations in gene expression. The highly invasive phenotype was intrinsic to the cells, independent of their environment, and was marked by transiently high levels of SEMA3C expression, as revealed by RNA-sequencing analysis. Furthermore, the invasive subpopulation drove the bulk dissemination of tumor cells to distal locations in a mouse model of melanoma. The transcription factor NKX2.2 regulated the proportion of invasive cells in the melanoma 1205Lu cell line. Furthermore, an overall tradeoff between proliferation and invasion in single cells was observed. Our results suggest that phenotypes like metastasis may arise from intrinsic differences stemming from non-genetic fluctuations between single cells.

cancer biology↗

bioRxiv2021

Pre-determined diversity in resistant fates emerges from homogenous cells after anti-cancer drug treatment

Even amongst genetically identical cancer cells, therapy resistance often only emerges from a very small subset of those cells. Much effort has gone into uncovering the molecular differences in rare individual cells in the initial population that may allow certain cells to become therapy resistant; however, comparatively little is known about variability in the resistant outcomes themselves. Here, we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically, and functionally distinct fate types. These different resistant types are largely predetermined by molecular differences between cells before addition of drug and not by extrinsic cell-specific microenvironmental factors. Changes in dose and kind of drug can, however, switch the resistant fate type of an initial cell, even resulting in the generation and elimination of certain fate types. Diversity in resistant fates was observed across several single-cell-derived cancer cell lines and types treated with a variety of drugs. Cell fate diversity as a result of variability in intrinsic cell states may be a generic feature of response to external cues.

systems biology↗