Protein kinases are crucial targets for cancer treatment as they orchestrate important signals for oncogenesis and are often aberrantly activated owing to genomic alterations. In the past two decades, multiple kinase inhibitors have been developed, including those that are clinically effective regardless of tumour location, provided that the tumour harbours the aberrantly activated kinase. Consequently, a biomarker-based therapy model, untethered from tumour histology and organ of origin, has been established, which has led to transformative regulatory approvals of tumour-agnostic kinase inhibitors such as larotrectinib, selpercatinib, dabrafenib–trametinib and pemigatinib. However, almost all such approvals are partial in nature, as they do not include both solid and haematological cancers, even if the kinase inhibitor has shown activity in both. Moreover, clinical trials to assess these compounds are challenging because genomic sequencing of hundreds or thousands of tumours may be required to find eligible patients whose malignancy bears the targeted genetic alterations. In this Review, we describe the precision medicine paradigm that has successfully launched tumour-agnostic drug development, concentrating on small-molecule inhibitors that target kinase pathway aberrations, and we discuss the challenges in developing tumour‐agnostic agents.
Over the last 30 years, NRF2 has evolved from being recognized as a transcription factor primarily involved in redox balance and detoxification to a well-appreciated master regulator of cellular proteostasis, metabolism and iron homeostasis. NRF2 plays a pivotal role in diverse pathologies, including cancer, and metabolic, inflammatory and neurodegenerative disorders. It exhibits a Janus-faced duality, safeguarding cellular integrity in normal cells against environmental insults to prevent disease onset, whereas in certain cancers, constitutively elevated NRF2 levels provide a tumour survival advantage, promoting progression, therapy resistance and metastasis. Advances in understanding the mechanistic regulation of NRF2 and its roles in human pathology have propelled the investigation of NRF2-targeted therapeutic strategies. This Review dissects the mechanistic intricacies of NRF2 signalling, its cross-talk with biological processes and its far-reaching implications for health and disease, highlighting key discoveries that have shaped innovative therapeutic approaches targeting NRF2.
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