A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.

Oncogenic KRAS is the key driver oncogene for several of the most aggressive human cancers. One key feature of oncogenic KRAS expression is an early increase in cellular reactive oxygen species (ROS) which promotes cellular transformation if cells manage to escape cell death, mechanisms of which remain incompletely understood. Here, we identify that expression of oncogenic as compared to WT KRAS in isogenic cellular systems renders cells more resistant to ferroptosis, a recently described type of regulated necrosis. Mechanistically, we find that cells with mutant KRAS show a specific lack of ferroptosis-induced lipid peroxidation. Interestingly, KRAS-mutant cells upregulate expression of ferroptosis suppressor protein 1 (FSP1). Indeed, elevated levels of FSP1 in KRAS-mutant cells are responsible for mediating ferroptosis resistance and FSP1 is upregulated as a consequence of MAPK and NRF2 pathway activation downstream of KRAS. Strikingly, FSP1 activity promotes cellular transformation in soft agar and its overexpression is sufficient to promote spheroid growth in 3D in KRAS WT cells. Moreover, FSP1 expression and its activity in ferroptosis inhibition accelerates tumor onset of KRAS WT cells in the absence of oncogenic KRAS in vivo. Consequently, we find that pharmacological induction of ferroptosis in pancreatic organoids derived from the LsL-KRAS^G12D expressing mouse model is only effective in combination with FSP1 inhibition. Lastly, FSP1 is upregulated in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) as compared to the respective normal tissue of origin and correlates with NRF2 expression in PDAC patient datasets. Based on these data, we propose that KRAS-mutant cells must navigate a ferroptosis checkpoint by upregulating FSP1 during tumor establishment. Consequently, ferroptosis-inducing therapy should be combined with FSP1 inhibitors for efficient therapy of KRAS-mutant cancers.

The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFR^T790M-negative but EGFR^G724S-positive subclones and osimertinib resistance. We demonstrate that EGFR^G724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFR^G724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFR^G724S-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFR^G724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFR^G724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.

Objective: Effective communication minimizes medical errors and leads to improved team performance while treating critically ill patients. Closed-loop communication is routinely applied in high-risk industries but remains underutilized in healthcare. Simulation serves as an educational tool to introduce, practice, and appreciate the efficacy of closed-loop communication. Methods: This observational before-and-after study investigates behavioral changes in communication among nurses brought on by simulation team training in a pediatric intensive care unit (PICU). The communication patterns of PICU nurses, who had no prior simulation experience, were observed during routine bedside care before and after undergoing in situ simulation. One month before and 1 and 3 months after simulation (intervention), 2 trained raters recorded nurse communications relative to callouts, uttered by the sender, and callbacks, reciprocated by the recipient. The impact of simulation on communication patterns was analyzed quantitatively. Results: Among the 15 PICU nurses included in this study, significant changes in communication behavior were observed during patient care after communication-focused in situ simulation. The PICU nurses were significantly less likely to let a callout go unanswered during clinical routine. The effect prevailed both 1 month (P = 0.039) and 3 months (P = 0.033) after the educational exposure. Conclusions: This observational before-and-after study describes the prevalence and pattern of communication among PICU nurses during routine patient care and documents PICU nurses transferring simulation-acquired communication skills into their clinical environment after a single afternoon of in situ simulation. This successful transfer of simulation-acquired skills has the potential to improve patient safety and outcome.