Lamolinara, A. | bioRxiv Science

bioRxiv2026

p140Cap enhances breast cancer chemosensitivity by limiting an ABCC1-enriched stem-like compartment via β-Catenin inhibition

Chemotherapy response in breast cancer is highly heterogeneous and influenced by tumor-intrinsic drivers of drug sensitivity, including cancer stem cell abundance. We previously reported that the scaffold protein p140Cap limits breast cancer stem cell traits and delays tumor progression. Here, we investigated the role of p140Cap in shaping sensitivity to chemotherapy in HER2-positive and triple-negative breast cancer. In preclinical and patient-derived models, p140Cap enhances chemotherapy response by increasing intracellular doxorubicin retention, DNA damage and subsequent apoptosis. Mechanistically, p140Cap constrained a doxorubicin-negative side population enriched for stem-like properties and elevated ABCC1 expression via inhibition of {beta}-Catenin signaling. Constitutively active {beta}-Catenin expression reversed this phenotype, whereas pharmacological inhibition of the Wnt/{beta}-Catenin pathway with IWR-1 or LGK-974 sensitized p140Cap-deficient tumors to chemotherapy. Clinically, analyses of breast cancer cohorts and patient-derived xenograft models identify p140Cap as predictive biomarker of chemotherapy response, proposing p140Cap-guided patient stratification, dose optimization and rational combination therapies.

cancer biology↗

bioRxiv2024

Enhancing PDAC Therapy: Decitabine-Olaparib Synergy Targets KRAS-Dependent Tumors

Current chemotherapies provide limited clinical benefits to patients with pancreatic ductal adenocarcinoma (PDAC), partly due to the lack of effective biomarkers for personalized therapy. KRAS activating mutations occur in almost 90% of PDAC cases, leading to a subset of tumors dependent on KRAS for survival (dKRAS). Assessing dKRAS in PDAC can be achieved using gene expression signature scores, independent of specific KRAS mutations, allowing for personalized therapies. Previous studies have shown that dKRAS-PDAC cells are more sensitive to the FDA-approved drug decitabine (DEC), although the mechanism remains unclear. While DEC is approved for hematological tumors, its repurposing in solid tumors poses challenges due to high-dose hematological side effects. Identifying optimal pharmacological approaches and response biomarkers is crucial for the successful clinical implementation of DEC in PDAC and other solid tumors. Our investigation revealed that low-dose DEC combined with the PARP inhibitor olaparib (OLA) enhances antitumor activity in dKRAS-PDAC. Mechanistically, DEC induces DNA damage and activates an ATR/ATM-mediated DNA damage response (DDR), with PARP1-mediated DNA repair playing a crucial role. Inhibiting PARP activity with OLA enhances antitumor activity, even in BRCA1/2wild-type and homologous recombination (HR)-proficient tumors, but it is ineffective in KRAS-independent tumors. Thus, transcriptomic-based KRAS dependency scores effectively predict the efficacy of combined therapy. Additionally, in dKRAS-PDAC tumors carrying a BRCA2 mutation, low-dose DEC enhances OLAs antitumor activity, completely inhibiting metastasis growth compared to single-drug treatments. Our findings support further clinical evaluation of DEC+OLA combination therapy in PDAC, particularly in dKRAS-positive tumors, irrespective of BRCA1/2 status. This approach extends the clinical benefit of OLA beyond BRCA status, addressing a limitation in targeted PARP inhibitor therapies. Furthermore, we highlight DDR as a key mechanism of action for DEC, beyond its role in gene expression regulation, underscoring the mode of action of this widely used anticancer drug.

cancer biology↗

bioRxiv2020

Resolvin D1 and D2 reduce SARS-Cov-2-induced inflammation in cystic fibrosis macrophages

Resolvins (Rv) are endogenous lipid autacoids that mediate resolution of inflammation and bacterial infections. Their roles in SARS-CoV-2 and COVID-19 are of considerable interest in the context of cystic fibrosis (CF) given the paucity of data regarding the effect of this virus on immune cells from individuals with CF. Here, we provide evidence for Rv biosynthesis and regulatory actions on CF macrophage inflammatory responses.

pathology↗