Ribociclib induces broad chemotherapy resistance and EGFR dependency in ESR1 wildtype and mutant breast cancer

While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating ESR1 gene mutations occurring in 15–40% of advanced cancers. Therefore, there is an urgent need to discover novel effective therapies that can eradicate cancer cells with aberrant ERα and to understand the cellular response underlying their action. Here, we evaluate the response of MCF7-derived, CRISPR-Cas9-generated cell lines expressing mutant ERα (Y537S) to a large number of drugs. We report sensitivity to numerous clinically approved inhibitors, including CDK4/6 inhibitor ribociclib, which is a standard-of-care therapy in the treatment of metastatic ERα-positive breast cancer and currently under evaluation in the neoadjuvant setting. Ribociclib treatment induces senescence in both wildtype and mutant ERα breast cancer models and leads to a broad-range drug tolerance. Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatmen

Population-specific variations of the genetic architecture of sex determination in wild European sea bass Dicentrarchus labrax L.

Among the different sex determination modalities exhibited by fish species, polygenic sex determination (PSD) may show variations in terms of genetic and environmental components between populations exposed/adapted to different environments. European sea bass (Dicentrarchus labrax) is an interesting model, combining both a PSD system and a genetic subdivision into an Atlantic and a Mediterranean lineage, with genetic substructures within the Mediterranean Sea. We produced experimental progeny crosses (N = 927) from broodstock sampled in four wild populations (North Atlantic, NAT; Western Mediterranean, WEM; North-Eastern Mediterranean, NEM; South-Eastern Mediterranean, SEM). There were less females than males in the progeny, both in the global dataset (32.5%) and within each paternal group (from 25.1% for NEM to 39.0% for WEM), with significant variation among populations, dams and sires. Sex, body weight (BW) and body length (BL) showed moderate heritability (0.52 ± 0.17, 0.46 ± 0.17, 0.34 ± 0.15, respectively). Sex was genetically correlated with BW and BL (rA sex/BW = 0.69 ± 0.12, rA sex/BL = 0.66 ± 0.13). The wGWAS performed both on the global dataset and within each paternal group revealed a different genetic architecture of sex determination between Atlantic and Mediterranean populations (9 QTLs found in NAT, 7 in WEM, 5 in NEM and 4 in SEM, with a cumulated variance explained of 27.04%, 21.87%, 15.89% and 12.10%, respectively) with a more similar genetic architecture among geographically close populations compared to geographically distant populations, consistent with the hypothesis of a population-specific evolution of polygenic sex determination systems in different environments

GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer

Pancreatic cancer is an aggressive malignancy with increasing incidence and poor prognosis due to its late diagnosis and intrinsic chemoresistance. Most pancreatic cancer patients present with locally advanced or metastatic disease characterized by inherent resistance to chemotherapy. These features pose a series of therapeutic challenges and new targets are urgently needed. Glycogen synthase kinase 3 beta (GSK3β) is a conserved serine/threonine kinase, which regulates key cellular processes including cell proliferation, DNA repair, cell cycle progression, signaling and metabolic pathways. GSK3β is implicated in non-malignant and malignant diseases including inflammation, neurodegenerative diseases, diabetes and cancer. GSK3β recently emerged among the key factors involved in the onset and progression of pancreatic cancer, as well as in the acquisition of chemoresistance. Intensive research has been conducted on key oncogenic functions of GSK3β and its potential as a druggable target; currently developed GSK3β inhibitors display promising results in preclinical models of distinct tumor types, including pancreatic cancer. Here, we review the latest findings about GSK-3β biology and its role in the development and progression of pancreatic cancer. Moreover, we discuss therapeutic agents targeting GSK3β that could be administered as monotherapy or in combination with other drugs to surmount chemoresistance. Several studies are also defining potential gene signatures to identify patients who might benefit from GSK3β-based therapeutic intervention. This detailed overview emphasizes the urgent need of additional molecular studies on the impact of GSK3β inhibition as well as structural analysis of novel compounds and omics studies of predictive biomarkers

Ribociclib Induces Broad Chemotherapy Resistance and EGFR Dependency in ESR1 Wildtype and Mutant Breast Cancer

While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating ESR1 gene mutations occurring in 15-40% of advanced cancers. Therefore, there is an urgent need to discover novel effective therapies that can eradicate cancer cells with aberrant ERα and to understand the cellular response underlying their action. Here, we evaluate the response of MCF7-derived, CRISPR-Cas9-generated cell lines expressing mutant ERα (Y537S) to a large number of drugs. We report sensitivity to numerous clinically approved inhibitors, including CDK4/6 inhibitor ribociclib, which is a standard-of-care therapy in the treatment of metastatic ERα-positive breast cancer and currently under evaluation in the neoadjuvant setting. Ribociclib treatment induces senescence in both wildtype and mutant ERα breast cancer models and leads to a broad-range drug tolerance. Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatment