Biology subjects

Gence, R.

Publications and source records attributed to Gence, R..

3 recordsLinked to original sources

bioRxiv2026

Persistent TOP1 cleavage complexes in drug-tolerant cells drive adaptive resistance to EGFR-targeted therapies in lung cancer

Resistance to targeted cancer therapies often arises from drug-tolerant cells (DTCs), which survive treatment by entering a non-proliferative state. Over time, DTCs can acquire mutations that contribute to cell reproliferation, but how non-proliferating DTCs accumulate such mutations remains unclear. Here, we show that EGFR inhibition in EGFR-mutated lung cancer transiently downregulates tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme that resolves abortive topoisomerase I cleavage complexes (TOP1ccs). In DTCs, elevated reactive oxygen species promote TOP1cc trapping, while TDP1 downregulation impairs their repair, driving TOP1cc accumulation, resistance mutation acquisition, and cell reproliferation. We further find that TDP1 expression is absent in approximately 25% of EGFR-mutated lung cancers. In TDP1-deficient cells, combining EGFR inhibition with a sublethal concentration of topotecan, which further increases TOP1ccs, abolishes cell reproliferation. Together, these findings establish persistent TOP1cc accumulation as a driver of therapy-induced mutagenesis linking drug tolerance to adaptive resistance, and reveal TDP1 loss as a targetable vulnerability in EGFR-mutated lung cancers. TeaserA drug-tolerant state that fuels mutagenesis and resistance also creates a transient vulnerability.

molecular biology↗

bioRxiv2024

Moesin activation controls bone resorption and tunneling nanotube-dependent osteoclast fusion

Cell-cell fusion is an evolutionarily conserved process that is essential for many functions, including fertilisation and the formation of placenta, muscle and osteoclasts, multinucleated cells that are unique in their ability to resorb bone. The mechanisms of osteoclast multinucleation involve dynamic interactions between the actin cytoskeleton and the plasma membrane that are still poorly characterized. Here, we found that moesin, a cytoskeletal linker protein member of the Ezrin/Radixin/Moesin (ERM) protein family, is activated during osteoclast maturation and plays an instrumental role in both osteoclast fusion and function. In mouse and human osteoclast precursors, moesin inhibition favors their ability to fuse into multinucleated osteoclasts. Accordingly, we demonstrated that moesin depletion decreases membrane-to-cortex attachment and enhances the formation of tunneling nanotubes (TNTs), F-actin-based intercellular bridges that we reveal here to trigger cell-cell fusion. Moesin also controls HIV-1- and inflammation-induced cell fusion. In addition, moesin regulates the formation of the sealing zone, the adhesive structure determining osteoclast bone resorption area, and thus controls bone degradation, via a {beta}3-integrin/RhoA/SLK pathway. Supporting our results, moesin-deficient mice present a reduced density of trabecular bones and increased osteoclast abundance and activity. These findings provide a better understanding of the regulation of cell-cell fusion and osteoclast biology, opening new opportunities to specifically target osteoclast activity in bone disease therapy.

cell biology↗

bioRxiv2022

Farnesyltransferase inhibition overcomes the adaptive resistance to osimertinib in EGFR-mutant NSCLC

Drug-tolerant "dormant" cells (DTC) have emerged as one of the major non-genetic mechanisms driving resistance to targeted therapy in lung cancer, although the sequence of events leading to entry and exit from dormancy remain poorly described. Here, we performed real-time monitoring of the cell cycle dynamics during the adaptive response to Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKi) in a panel of EGFR-mutated lung cancer cell lines. We identified a rare population of S/G2 cycling cells (referred to as early escapers) that emerged in the first hours of treatment amongst stably arrested and progressively dying G1 cells. We determined that early escapers evolved from a non-proliferative differentiated alveolar type 1 (AT1) phenotype which was invariably associated with cytoskeletal remodeling through Rho/ROCK pathway activation. Using a panel of Rho-pathway inhibitors, we found that the farnesyltransferase inhibitor tipifarnib induced a complete clearance of EGFR-TKi-induced DTC thus fully preventing relapse in vitro. Using a xenograft model and a PDX model of EGFRL858R/T790M lung cancer, co-treatment with tipifarnib prevented relapse to osimertinib for up to 6 months with no evidence of toxicity. Among the farnesylated proteins regulated during osimertinib treatment, concomitant inhibition of RHOE and LaminB1 was sufficient to recapitulated FTIs effect. Osimertinib and tipifarnib co-treatment completely suppressed the emergence of AT1 phenotype, prevented mitosis of S/G2-treated cells and increased the apoptotic response through activation of ATF4-CHOP-dependent Integrated Stress Response (ISR) pathway. Our data strongly support the use of tipifarnib in combination with osimertinib in patients to effectively and durably prevent relapse.

cancer biology↗