Biology subjects

Will, M.

Publications and source records attributed to Will, M..

3 recordsLinked to original sources

bioRxiv2024

Homologous recombination deficiency and tumor suppressor heterozygosity mediate resistance to front-line therapy in breast cancer

The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, but their combined biologic and clinical significance has not been evaluated. To assess the role of germline-somatic interactions on outcomes in routine practice, we developed an integrated clinicogenomic pipeline to analyze the genomes of over 4,500 patients with breast cancer. We find that germline (g)BRCA2-associated tumors are enriched for RB1 loss-of-function mutations and manifest poor outcomes on standard-of-care, front-line CDK4/6 inhibitor (CDK4/6i) combinations. Amongst these tumors, gBRCA2-related homologous recombination deficiency (HRD) as well as baseline RB1 LOH status promote acquisition of RB1 loss-of- function mutations under the selective pressure of CDK4/6i, causing therapy resistance. These findings suggest an alternative therapeutic strategy using sequential targeting of HRD in gBRCA- associated breast cancers through PARP inhibitors prior to CDK4/6i therapy to intercept deleterious RB1-loss trajectories and thus suppress the emergence of CDK4/6 inhibitor resistance. More broadly, our findings demonstrate how germline-somatic driven genomic configurations shape response to systemic therapy and can be exploited therapeutically as part of biomarker-directed clinical strategies.

genomics↗

bioRxiv2023

Imprecise perception of hand position during early motor adaptation

Localizing ones body parts is important for movement control and motor learning. Recent studies have shown that the precision with which people localize their hand places constraints on motor adaptation. While these studies have assumed that hand localization remains equally precise across learning, we show that precision decreases rapidly during early motor learning. In three experiments, healthy young participants (n=92) repeatedly adapted to a 45{degrees} visuomotor rotation for a cycle of two to four reaches, followed by a cycle of two to four reaches with veridical feedback. Participants either used an aiming strategy that fully compensated for the rotation (experiment 1), or always aimed directly at the target, so that adaptation was implicit (experiment 2). We omitted visual feedback for the last reach of each cycle, after which participants localized their unseen hand. We observed an increase in the variability of angular localization errors when subjects used a strategy to counter the visuomotor rotation (experiment 1). This decrease in precision was less pronounced in the absence of re-aiming (experiment 2), and when subjects knew that they would have to localize their hand on the upcoming trial, and could thus fully allocate attention to hand position (experiment 3). We propose that attention to vision during strategic re-aiming decreases the precision of perceived hand position. We discuss how these dynamics in precision during early motor learning could impact on motor control, and shape the interplay between implicit and strategy-based motor adaptation. NEW & NOTEWORTHYRecent studies indicate that the precision with which people localize their hand limits implicit visuomotor learning. We found that localization precision is not static, but decreases early during learning. This decrease is pronounced when people apply a re-aiming strategy to compensate for a visuomotor perturbation, and diminishes when the hand is fully attended. We propose that these attention-dependent dynamics in position sense during learning may influence how implicit and strategy-based motor adaption interact.

neuroscience↗

bioRxiv2023

Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion

Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a clinically-annotated cohort of patients with metastatic HR+ breast cancer, we identified TP53 loss (28.8%) and MDM2 amplification (6.7%) to be associated with lack of long-term disease control. Human breast cancer models revealed that p53 loss did not affect CDK4/6 activity or G1-blockade, but instead promoted drug-insensitive p130 phosphorylation by CDK2. Persistence of phospho-p130 prevented DREAM complex assembly, enabling cell cycle reentry and tumor progression. Inhibitors of CDK2 could overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically-diverse HR+ breast cancers.

cancer biology↗