Biology subjects

Whitman, A. A.

Publications and source records attributed to Whitman, A. A..

5 recordsLinked to original sources

bioRxiv2026

Vulnerability of triple negative breast cancer to daraxonrasib pan-RAS(on) inhibition

Triple-Negative Breast Cancer (TNBC) is a clinical subtype where aberrant expression of receptor tyrosine kinases (RTKs) leads to the activation of the RAS-RAF-MEK-ERK pathway contributing to tumor progression. Therapies targeting components of the RAF-MEK-ERK pathway in TNBC have been disappointing due to rapid onset of adaptive reprogramming of the RTK landscape leading to pathway reactivation. To overcome the dynamic heterogeneity of RTK expression and their convergence in activating RAS, treatment with the pan-RAS(on) inhibitor daraxonrasib (RMC-6236), which inhibits RAS-GTP regulation of RAF kinases, inhibited proliferation independent of TNBC kinotype or oncogenic RAS mutation in three of four TNBC cell lines in vitro and two patient-derived TNBC xenografts in mice. Daraxonrasib in combination with the MEK inhibitor trametinib prevented reactivation of the RAF-MEK-ERK pathway observed with each inhibitor alone and further enhanced inhibition of tumor growth in TNBC cell lines and xenografts. Inhibiting pan-RAS(on) RAS-GTP, with daraxonrasib, alone or in combination with a MEK inhibitor, provides a new strategy for the treatment of TNBC that inhibits RTK activation of the RAS-RAF-MEK-ERK pathway and tumor proliferation.

cancer biology↗

bioRxiv2026

Non-Genetic Mechanisms of Fractional Resistance to Abemaciclib in Dedifferentiated Liposarcoma.

Dedifferentiated liposarcoma is a rare mesenchymal malignancy driven by amplification of chromosome 12q13-15, which includes the oncogenes CDK4 and MDM2. CDK4 amplification provides a rationale for targeted therapy with CDK4/6 inhibitors, and abemaciclib has shown the most durable activity reported to date in this disease. Clinical responses, however, are incomplete and often transient, and the cellular features that allow tumor cells to continue proliferating during treatment are not well understood. To address this gap, we performed multiplexed single-cell imaging to quantify 17 cell-cycle regulators in both dedifferentiated liposarcoma cell line Lipo246 and surgically resected primary human cells exposed to abemaciclib. Both models contained a subpopulation of cells that retained phosphorylated retinoblastoma protein, a marker of cell proliferation, at the highest abemaciclib doses. These fractionally resistant cells were defined by selective enrichment of cyclin-dependent kinase 2 (CDK2), cyclin B1, and phosphorylated ribosomal protein S6 (pS6), and showed enhanced sensitivity to the CDK2 inhibitor, tagtociclib. Together, these findings reveal nongenetic cell cycle plasticity as a mechanism of escape from CDK4/6 inhibition in dedifferentiated liposarcoma and nominate CDK2 and the PI3K-mTOR pathway as candidate targets for combination therapy.

cancer biology↗

bioRxiv2024

Kinase Plasticity in Response to Vandetanib Enhances Sensitivity to Tamoxifen and Identifies Co-Treatment Strategies in Estrogen Receptor Positive Breast Cancer

Resistance to endocrine therapy (ET) is common in estrogen receptor-positive (ER+) breast cancer. Multiple studies have demonstrated that upregulation of MAPK signaling pathways contributes to ET resistance. Herein we show that vandetanib treatment suppresses MAPK signaling and enhances sensitivity to ET across ET-sensitive and ET-resistant ER+ cell lines and patient derived organoids. Vandetanib treatment reprograms transcription toward a less proliferative, more estrogen responsive, Luminal-A like state by enriching ER chromatin binding at canonical estrogen response elements. Multiplexed kinase inhibitor beads-mass spectrometry (MIB/MS) revealed kinase network reprogramming, including upregulation of PI3K and HER2 activity, as shared adaptive resistance mechanisms to vandetanib treatment. Co-treatment with the HER2 inhibitor lapatinib, further enhanced sensitivity to vandetanib. Using an operating room-to-laboratory short-term ex-vivo assay coupled to single-cell RNA sequencing, we demonstrate conserved gene expression changes in primary tumor cells, including increased HER2 activity signatures, following vandetanib treatment. Vandetanib sensitivity signatures were generated from cell line and primary human tumor cells which correlate with vandetanib sensitivity in ER+ patient-derived organoid and xenograft models. Future clinical trials of vandetanib in ER+ breast cancer should include rationally designed co-treatments based on adaptive resistance pathways, including HER2, and evaluate response signatures as biomarkers predicting patients most likely to benefit. SIGNIFICANCEVandetanib enhances sensitivity to tamoxifen in ER+ breast cancer by reprograming ER gene regulation and kinase signaling networks which define gene expression signatures associated with response and identify targetable adaptive resistance pathways.

cancer biology↗

bioRxiv2023

Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in ER+/HER2- breast tumor cells. Although these drugs have significantly improved patient outcomes in metastatic breast cancers, a small percentage of tumor cells continues to divide in the presence of palbociclib--a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcome. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant tumor cells both in a cell culture model of ER+/HER2- breast cancer as well as live primary tumor cells resected from a patient. We found that tumor cells capable of proliferating in the presence of palbociclib showed both expected (e.g., CDK2, E2F1) and unexpected (e.g., Cdt1, p21, cyclin B1) shifts in core cell cycle regulators. Notably, resistant cells in both tumor models showed premature enrichment of the G1 regulators E2F1 and CDK2 protein and, unexpectedly, the G2/M regulator cyclin B1 just before cell cycle entry, suggesting that resistant cells may use noncanonical mechanisms to overcome CDK4/6 inhibition. Using computational data integration and trajectory inference approaches, we show how plasticity in cell cycle regulators gives rise to alternate cell cycle "paths" that allow individual ER+/HER2- tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.

cancer biology↗

bioRxiv2023

Tamoxifen Response at Single Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors

In ER+/HER2- breast cancer, multiple measures of intra-tumor heterogeneity are associated with worse response to endocrine therapy. To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live human tumors and normal breast specimens immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from 3 distinct resistant subpopulations are prognostic in large cohorts of ER+ breast cancer patients and enriched in endocrine therapy resistant tumors. This novel ex vivo model system now provides a foundation to define responsive and resistant sub-populations within heterogeneous tumors, to develop precise single cell-based predictors of response to therapy, and to identify genes and pathways driving resistance to therapy.

cancer biology↗