Biology subjects

Westermaier, Y.

Publications and source records attributed to Westermaier, Y..

4 recordsLinked to original sources

bioRxiv2026

DUSP4 knockdown in BRAF V600E mutant colorectal cancer induces cell cycle arrest and halts tumor growth

Oncogenic signaling in cancer cells is essential for proliferation, and its disruption, either through inhibition or overactivation, can provide therapeutic opportunities. Dual specificity phosphatase 4 (DUSP4), a negative regulator of the MAPK pathway that dephosphorylates ERK, has been proposed as a potential target; however, its therapeutic relevance has not been evaluated in vivo. In this study, we show that DUSP4 knock-down induces G1 cell cycle arrest and reduces proliferation in BRAFV600E-mutant and BRAF inhibitor-resistant colorectal cancer models, both in vitro and in vivo, and induces a rapid DUSP5-mediated adaptive response. While treatment achieved tumor stasis indicating disease control, it did not yield tumor regression, suggesting that DUSP4 may have limited efficacy as a monotherapy target in cancer.

genetics↗

bioRxiv2024

Molecular Simulations Meet Personalized Medicine. The Mechanism of Action of ClC-5 Antiporter and the Origin of Dent's Disease

ClC-5 is a Cl-/H+ antiporter crucial for the homeostasis of the entire organism, and whose functional deficiencies cause pathologies such as Dents disease, a rare genetic disorder that can have lethal consequences. While the clinical aspects of the pathology are known, its molecular basis is elusive, which hampers the development of potential therapies. We present here a systematic study, where we explore the mechanism of transport of ClC-5, deciphering the choreography of structural changes required for the transport of chloride ions and protons in opposing directions. Once the mechanism is determined, we explore how the 523{Delta}Val deletion linked to Dents disease hampers the correct functioning of the transporter, despite having a very minor structural impact. Our study highlights how state-of-the-art simulation methods can provide information on the origin of rare diseases and serve as a tool in personalized medicine.

biophysics↗

bioRxiv2024

Confounding factors in targeted degradation of short-lived proteins

Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but to what extent it influences target protein degradation has not been systematically explored. Using mathematical modelling of protein degradation, we demonstrate that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a degrader agent which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required to conclude that a novel agent works as a bona fide targeted protein degrader.

cancer biology↗

bioRxiv2022

Prediction Of The Impact Of Genetic Variability On Drug Sensitivity For Clinically Relevant EGFR Mutations

Mutations in the kinase domain of the Epidermal Growth Factor Receptor (EGFR) can be drivers of cancer and also trigger drug resistance in patients under chemotherapy treatment based on kinase inhibitors use. A priori knowledge of the impact of EGFR variants on drug sensitivity would help to optimize chemotherapy and to design new drugs effective against resistant variants. To this end, we have explored a variety of in silico methods, from sequence-based to state-of-the-art atomistic simulations. We did not find any sequence signal that can provide clues on when a drug-related mutation appears and what will be the impact in drug activity. Low-level simulation methods provide limited qualitative information on regions where mutations are likely to produce alterations in drug activity and can predict around 70% of the impact of mutations on drug efficiency. High-level simulations based on non-equilibrium alchemical free energy calculations show predictive power. The integration of these state-of-the-art methods in a workflow implementing an interface for parallel distribution of the calculations allows its automatic and high-throughput use, even for researchers with moderate experience in molecular simulations.

biochemistry↗