Biology subjects

Facchinetti, F.

Publications and source records attributed to Facchinetti, F..

3 recordsLinked to original sources

bioRxiv2026

mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal subversion

Targeted therapies for KRAS-mutant non-small lung cancer (NSCLC) have shown promising clinical results, however, incomplete tumoral responses and the inevitable emergence of therapeutic resistance remain critical challenges. Here we identify mSWI/SNF chromatin remodeling complexes as critical determinants of (EMT)-mediated KRAS inhibitor inefficacy and resistance in KRAS G12C lung cancers. Treatment with the clinical-grade SMARCA4/2 inhibitor, FHD-286, dampens EMT-mediated acquired resistance in drug-responsive models and similarly resensitizes drug-refractory models by rewiring mSWI/SNF chromatin localization and activities that modulate epithelial transcriptional programs and cell state. Further, synergistic mSWI/SNF and KRAS inhibitor combination treatment sensitizes non-G12C KRAS-mutant NSCLC cells to pan-RAS and G12D-specific inhibitors. Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance.

cancer biology↗

bioRxiv2023

Transferrin Receptor Targeting Chimeras (TransTACs) for Membrane Protein Degradation

Cancer cells require high levels of iron for rapid proliferation, leading to a significant upregulation of the iron carrier protein Transferrin Receptor (TfR) on their cell surface. Leveraging this phenomenon and the exceptionally fast endocytosis rate of TfR, we introduce Transferrin Receptor TArgeting Chimeras (TransTAC), a novel molecular archetype for membrane protein degradation in cancers and other cell types. TransTACs repurpose the naturally recycling receptor TfR1 for protein degradation. To accomplish this, we utilized a combination of protein engineering strategies to redirect the target protein from recycling-endosome trafficking to lysosomal degradation. We show that TransTACs can highly efficiently degrade a diverse range of single-pass, multi-pass, native, or synthetic membrane proteins, establishing new possibilities for targeted cancer therapy.

bioengineering↗

bioRxiv2020

SDF-1/CXCR4 inhibition prevents paradoxical generation of cisplatin-induced pro-metastatic niches

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite its ineffectiveness in long-term control of metastasis. Here, we uncover the interconnected pathways subtending cisplatin-induced metastasis promotion. We report that cisplatin treatment of tumor-free mice results in bone-marrow expansion of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM) concomitantly with increased levels in the lungs of stromal SDF-1, the CXCR4 ligand. In experimental metastasis assays, cisplatin-induced IM favor tumor cells extravasation and expansion of CD133+CXCR4+ metastasis initiating cells (MICs), facilitating lung metastasis formation. At the primary tumor, cisplatin reduces tumor size but induces tumor release of SDF-1 triggering MICs expansion and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IM at SDF-1-enriched distant sites also promotes spontaneous metastasis. Combination treatment with a CXCR4 inhibitor prevents cisplatin-induced IM/MICs recruitment and interaction thus precluding metastasis overgrowth. Finally, we observe in NSCLC patients specimens that SDF-1 levels are higher in platinum-treated samples and correlate with worse outcome. Our findings suggest a possible novel combination therapy based on CXCR4 blockade to control metastatic disease, paradoxically promoted by cisplatin.

cancer biology↗