Grace Goodhart

Abstract RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 61 1 . Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer 2,3 . Nevertheless, KRAS G12C mutations account for only around 15% of KRAS -mutated cancers 4,5 , and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations ( KRAS G12X ). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRAS G12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS -mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world's deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms.

Abstract Humidity levels, like light and temperature, fluctuate daily yet are less predictable; however, whether humidity can entrain circadian clocks and synchronize animal behaviors with environmental variations remains unknown. Here, we investigate the circadian humidity entrainment in various insects across multiple orders. Insect species respond to humidity cycles with distinct patterns, some active during wet periods or at the arid-humid transition. When the humidity cue is removed, most species continue to show rhythmic activity associated with the previous arid-humid (AH) cycles. Fruit flies shift their activity accordingly when humidity cycles are altered and remain in the new rhythms under the following free-running conditions (FRC; constant humidity, HH). Moreover, Drosophila clock and hygrosensation mutants lack rhythmic activity during (AH) and after humidity entrainment (FRC with HH), indicating that core clock components and hygrosensors are essential for circadian entrainment. Our findings provide strong evidence that humidity is likely to serve as a potential zeitgeber for circadian entrainment in most, but not all, insect systems and will likely have broad applicability and importance across animal systems. While light and temperature act as the primary zeitgebers, understanding the mechanisms of humidity entrainment will help us better interpret the behavioral patterns of terrestrial animals, particularly those susceptible to dehydration. One Sentence Summary: Humidity entrainment of the circadian clock synchronizes insect activity to environmental changes.