Persister cell plasticity in tumour drug resistance.

The emergence of therapeutic resistance remains a formidable barrier to durable responses by cancer patients and is a major cause of cancer-related deaths. It is increasingly recognized that non-genetic mechanisms of acquired resistance are important in many cancers. These mechanisms of resistance rely on inherent cellular plasticity where cancer cells can switch between multiple phenotypic states without genetic alterations, providing a dynamic, reversible resistance landscape. Such mechanisms underlie the generation of drug-tolerant persister (DTP) cells, a subpopulation of tumour cells that contributes to heterogeneity within tumours and that supports therapeutic resistance. In this review, we provide an overview of the major features of DTP cells, focusing on phenotypic and metabolic plasticity as two key drivers of tolerance and persistence. We discuss the link between DTP cell plasticity and the potential vulnerability of these cells to ferroptosis. We also discuss the relationship between DTP cells and cells that survive the induction of apoptosis, a process termed anastasis, and discuss the properties of such cells in the context of increased metastatic potential and sensitivity to cell death mechanisms such as ferroptosis.

PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrPC could be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNP gene encoding PrPC is associated with EMT. By manipulating the levels of PrPC in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrPC is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrPC operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrPC levels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNP levels increase with TKI resistance and that reducing PRNP expression sensitizes cells to osimertinib. Finally, we found that plasma PrPC levels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrPC as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrPC levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrPC-targeted therapies for EGFR-mutated NSCLC patients with TKI failure.

Co-vulnerabilities of inhibiting carbonic anhydrase IX in ferroptosis-mediated tumor cell death.

The tumour-associated carbonic anhydrases (CA) IX and XII are upregulated by cancer cells to combat cellular and metabolic stress imparted by hypoxia and acidosis in solid tumours. Owing to its tumour-specific expression and function, CAIX is an attractive therapeutic target and this has driven intense efforts to develop pharmacologic agents to target its activity, including small molecule inhibitors. Many studies in multiple solid tumour models have demonstrated that targeting CAIX activity with the selective CAIX/XII inhibitor, SLC-0111, results in anti-tumour efficacy, particularly when used in combination with chemotherapy or immune checkpoint blockade, and has now advanced to the clinic. However, it has been observed that sustainability and durability of CAIX inhibition, even in combination with chemotherapy agents, is limited by the occurrence of adaptive resistance, resulting in tumour recurrence. Importantly, the data from these models demonstrates that CAIX inhibition may sensitize tumour cells to cytotoxic drugs and evidence now points to ferroptosis, an iron-dependent form of regulated cell death (RCD) that results from accumulation of toxic levels of phospholipid peroxidation as a major mechanism involved in CAIX-mediated sensitization to cancer therapy. In this mini-review, we discuss recent advances demonstrating the mechanistic role CAIX plays in sensitizing cancer cells to ferroptosis.