Biology subjects

Garraway, L. A.

Publications and source records attributed to Garraway, L. A..

4 recordsLinked to original sources

bioRxiv2026

Genomic, Clinical, and Spatial Predictors of Durable Response to BRAF/MEK Inhibition in BRAF-Mutant Melanoma

BRAF-targeted therapy (BRAFi/MEKi) and immune checkpoint blockade (anti-PD-1/anti-CTLA-4) have transformed the treatment of BRAF-mutant metastatic melanoma. While most patients who respond to targeted therapy eventually progress, a subset derives durable benefit, and biomarkers to identify this subset would inform optimal treatment selection. In this study, we analyzed pre-treatment tumor samples from a clinically annotated cohort of 155 patients with BRAF-mutant metastatic melanoma treated with first-line BRAFi/MEKi and followed for up to five years. We stratified patients into durable responders (PFS [≥] 24 months) and rapid progressors (PFS < 6 months with progression) and found that a global metric of tumor genomic heterogeneity, rather than individual gene alterations, distinguished these groups. Combining genomic heterogeneity with baseline tumor burden (e.g., lactate dehydrogenase (LDH) or radiographic lesion dimensions), we developed a parsimonious model that predicted durable responders with high precision and specificity. Notably, the analogous population of patients treated instead with immunotherapy were not durable responders, suggesting that the selected predictors of durable responders are targeted therapy specific. Spatial profiling of a subset of pre-treatment biopsies (n = 47) demonstrated that high intratumoral, but not peritumoral, CD8+ T-cell infiltration correlated with prolonged survival on BRAF-targeted therapy and served as an independent predictive factor when considered with genomic heterogeneity and features of clinical tumor burden. Together, these findings highlight the distinct baseline intrinsic and extrinsic features underlying durable response to BRAF-targeted therapy and support their potential implication in guiding treatment selection for patients with BRAF-mutant metastatic melanoma. One-Sentence SummaryIntegrated clinical, tumor genomic, and immune microenvironmental features predict durable responses to BRAF-targeted therapy.

cancer biology↗

bioRxiv2026

Spatiotemporal profiling reveals the role of inflammatory niche in driving prostate cancer

Prostate cancer (PCa) is a lethal malignancy that displays profound resistance to immune checkpoint blockade (ICB), via mechanisms that are poorly understood. Here, we investigate the causes of CD8 T cell exhaustion and mechanisms of tumor progression in a PCa animal model, by single cell and spatial profiling, along a time course, following orthotopic transplantation of RB1/TP53/PTEN-deficient mouse organoids, competent to express neoantigens. The resulting tumors were castration resistant, consisting of largely basal and L2 malignant cells with upregulated inflammatory gene programs, and a specific spatial distribution of macrophages, cancer associated fibroblast (CAF) subtypes, and CD8 T-cells that was not previously reported. Using Zman-seq, we demonstrate that the effector function of tumor-infiltrating CD8 T cells was rapidly impaired as early as 24hrs after their infiltration, likely driven by signals from proinflammatory macrophages, Ccl2-Jak2+ inflammatory CAFs, and malignant basal cells, thus driving resistance to ICB. Interestingly, dual blockade of JAK1/2 and PD1 induced potent anti-tumor effects in tumor epithelial cells, decreased malignant epithelial cells and pro-inflammatory macrophages, and increased the proportion of normal (Pi16+) fibroblasts in the TME. Our results underscore the therapeutic potential of targeting JAK1/2 to enhance the efficacy of ICB, providing a rationale for clinical investigation of this combination in PCa.

cancer biology↗

bioRxiv2020

Highly multiplexed quantitative phosphosite assay for biology and preclinical studies

Reliable methods to quantify dynamic signaling changes across diverse pathways are needed to better understand the effects of disease and drug-treatment in cells and tissues but are presently lacking. Here we present SigPath, a targeted mass spectrometry (MS) assay that measures 284 phosphosites in 200 phosphoproteins of biological interest. SigPath probes a broad swath of signaling biology with high throughput and quantitative precision. We applied the assay to investigate changes in phospho-signaling in drug-treated cancer cell lines, breast cancer preclinical models and human medulloblastoma tumors. In addition to validating previous findings, SigPath detected and quantified a large number of differentially regulated phosphosites newly associated with disease models and human tumors at baseline or with drug perturbation. Our results highlight the potential of SigPath to monitor phosphoproteomic signaling events and to nominate mechanistic hypotheses regarding oncogenesis, response and resistance to therapy.

cancer biology↗

bioRxiv2019

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

Clinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for [~]5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these--RAS activation, AKT activation, and AURKA activation--have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients. SignificanceWe identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ MBC.

cancer biology↗