Biology subjects

Monast, A.

Publications and source records attributed to Monast, A..

3 recordsLinked to original sources

bioRxiv2025

EZH2 Inhibition Induces an Integrated Stress Response Driving Glutamine-Dependent Vulnerability in TNBC

EZH2, the catalytic subunit of Polycomb Repressive Complex II, is overexpressed and associated with poor prognosis in triple-negative breast cancer (TNBC). Although EZH2 inhibition induces significant changes in chromatin landscapes and gene expression, it has a limited impact on the growth of TNBC models, suggesting adaptive compensatory mechanisms. Here, we demonstrate that EZH2 inhibition leads to the accumulation of misfolded proteins and double-stranded RNA (dsRNA), triggering an essential integrated stress response (ISR) through PKR and PERK activation. By inducing ISR-mediated ATF4 activation, EZH2 inhibition enhances amino acid flux and promotes glutaminolysis, in turn activating mTOR signaling to support TNBC cell survival. Pharmacological targeting of this metabolic adaptation with a glutaminase (GLS) inhibitor in combination with EZH2 inhibition significantly impairs TNBC cell proliferation and tumor growth. These findings reveal a stress-driven metabolic adaptation that sustains TNBC survival upon EZH2 blockade and highlight inhibition of this pathway as a strategy to enhance the efficacy of EZH2 inhibitors in TNBC.

cancer biology↗

bioRxiv2025

ATR and PKMYT1 inhibition re-sensitize a subset of TNBC patient-derived models to carboplatin inducing mitotic catastrophe

Triple negative breast cancer (TNBC) is associated with poor prognosis and is mainly treated with chemotherapy-based regimens, often including carboplatin. Resistance to carboplatin is a common clinical issue that is either initially present or develops with treatment. Overcoming this resistance is a significant clinical challenge, which highlights the need for novel therapeutic strategies. We used a pooled shRNA screening approach with a chemoresistant TNBC patient-derived xenograft (PDX) cell (PDXC) line to identify targets whose knockdown would enhance the efficacy of carboplatin. This screening led to the identification of the ATR (ataxia telangiectasia and Rad3-related) gene as a key therapeutic vulnerability. Inhibiting ATR with BAY1895344 or AZD6738 re-sensitized carboplatin-resistant PDXCs and PDXs to carboplatin, resulting in an increase in DNA damage, and apoptosis. ATR inhibition disrupts the dependence of carboplatin-resistant cells on the S and G2/M checkpoints for DNA repair, leading to mitotic catastrophe. We further found that the addition of ATR inhibitors to carboplatin reversed a FOXM1-targeted gene program enabling premature passage into mitosis. Moreover, targeting PKMYT1, a regulator of cyclin-dependent kinase 1 (CDK1) controlling the G2/M checkpoint, through knockdown or with the novel PKMYT1 inhibitor RP-6306, also enhanced carboplatin efficacy in our TNBC PDXC. Molecular factors associated with response to the ATR inhibitor/carboplatin combination included low RNA levels of PKMYT1. These results underscore the pivotal roles of ATR and PKMYT1 in mediating resistance to carboplatin in TNBC and support targeting these pathways to overcome carboplatin resistance in this disease.

cancer biology↗

bioRxiv2021

Met-HER3 crosstalk supports proliferation via MPZL3 in MET-amplified cancer cells

Receptor tyrosine kinases (RTKs) are recognized as targets of precision medicine in human cancer upon their gene amplification or constitutive activation, resulting in increased downstream signal complexity including heterotypic crosstalk with other RTKs. The Met RTK exhibits such reciprocal crosstalk with several members of the human EGFR (HER) family of RTKs when amplified in cancer cells. We show that Met signaling converges on HER3 tyrosine phosphorylation across a panel of seven MET-amplified cancer cell lines and that HER3 is required for cancer cell expansion and oncogenic capacity in-vitro and in-vivo. Gene expression analysis of HER3-depleted cells identified MPZL3, encoding a single-pass transmembrane protein, as a HER3-dependent effector in multiple MET-amplified cancer cell lines. MPZL3 interacts with HER3 and MPZL3 loss phenocopies HER3 loss in MET-amplified cells, while MPZL3 overexpression rescues proliferation upon HER3 depletion. Together, these data support an oncogenic role for a HER3-MPZL3 axis in MET-amplified cancers.

cancer biology↗