RAS is one of the most frequently mutated genes in human cancers, present in about 20 percent of all cases. Its protein product acts as a master regulator of cell proliferation by initiating multiple downstream signalling cascades. Oncogenic mutations lock RAS protein in an active, GTP-bound state, relentlessly promoting cell division and tumorigenesis. Despite being a key cancer driver, directly targeting RAS has long eluded drug developers due to its high affinity for GTP/GDP and the smooth surfaces devoid of good binding pockets.

Instead, the research teams focused on a critical effector of RAS: the phosphoinositide 3-kinase enzyme PI3K, which propagates signals essential for cell growth and survival. However, indiscriminate inhibition of PI3K has posed significant clinical challenges because this enzyme also participates in vital functions like insulin signalling. Inhibitors that block PI3K broadly often incur metabolic toxicities such as hyperglycemia, limiting their therapeutic window.

To solve this conundrum, scientists employed a combination of sophisticated chemical biology methods and selective compound screening to identify molecules capable of covalently binding near the RAS-binding domain of PI3Kα isoform. These small molecules irreversibly attach to specific amino acid residues at the PI3K surface, effectively occluding the RAS binding site. Remarkably, this selectivity preserves PI3K’s ability to engage with other interaction partners, such as those in the insulin signalling axis, thereby reducing systemic side effects.

A bespoke biochemical assay developed at the Crick Institute enabled the verification that these covalent inhibitors disrupted the PI3K-RAS interaction with high specificity. Structural and functional characterizations confirmed that the compounds prevent the pathogenic activation loop driven by mutant RAS without compromising normal enzyme activity necessary for homeostasis. This targeted mechanism represents a major leap forward in precision oncology.

The in vivo efficacy of one leading compound was judiciously evaluated in mouse models engineered to develop RAS-mutated lung tumors. Treatment led to significant arrest of tumor progression without detectable increases in blood glucose levels. This outcome underscores the concept that uncoupling RAS-dependent oncogenic signalling from PI3K can suppress tumors effectively while sparing healthy physiology, a milestone in mitigating the therapy-limiting toxicities observed with previous PI3K inhibitors.

Further investigations demonstrated that combining the PI3K-RAS interaction blocker with other drugs targeting parallel nodes within the RAS pathway resulted in synergistic and durable tumor control. The combination therapies enhanced suppression of tumor growth beyond the capability of single agents, providing a compelling rationale for multi-modal treatment regimens leveraging pathway redundancies to overcome cancer resistance mechanisms.

The scope of the drug’s utility expanded unexpectedly when researchers explored its effects against HER2-driven tumors, commonly found in breast cancer and characterized by overexpression of the HER2 receptor tyrosine kinase. Since HER2 also signals via PI3K, but operates independently of RAS, the inhibitor nonetheless blocked PI3K-driven tumor growth in these models. This intriguing discovery implies the drugs could serve as versatile therapeutics across a wider spectrum of cancers harboring mutations in either RAS or HER2 oncogenes.

Following these promising preclinical results, the lead compound has entered Phase 1 clinical trials designed to assess safety, tolerability, and preliminary efficacy in patients with tumors driven by RAS or HER2 mutations. The trial will also investigate whether administering the drug in combination with other agents targeting RAS-associated pathways enhances therapeutic outcomes. The initiation of this clinical evaluation represents a significant translational achievement stemming from deep mechanistic insights into protein-protein interactions and covalent drug design.

Julian Downward, Principal Group Leader at the Francis Crick Institute, highlighted the perseverance required to address one of oncology’s most challenging targets: “Our journey to disrupt RAS-driven signalling without harmful side effects reflects decades of fundamental biology research and innovative chemistry. The ability to selectively prevent RAS from binding PI3K while preserving other cellular functions exemplifies how nuanced targeting can unlock new treatment avenues.”

Matt Patricelli, Chief Scientific Officer at Vividion Therapeutics, emphasized the transformative potential of this discovery for drug development: “These covalent inhibitors open a fresh paradigm for targeting oncogenic signalling complexes. By precisely blocking pathological protein interactions rather than entire enzymes, we have created molecules that can thwart tumor growth while maintaining normal cellular processes. Seeing this science advance into the clinic is truly rewarding.”

This breakthrough exemplifies the power of combining chemical biology, structural insights, and rigorous preclinical validation to overcome long-standing barriers in drug discovery. Should clinical trials validate safety and efficacy in humans, these compounds offer hope for improved therapies that can more effectively combat cancers driven by RAS and HER2 mutations without the burden of debilitating side effects. The approach also lays the groundwork for the design of next-generation molecular glues and inhibitors that selectively modulate oncogenic signalling pathways with unprecedented precision.

The Francis Crick Institute continues its mission to translate fundamental scientific insights into impactful medical advances that can save and improve lives. This collaboration with Vividion Therapeutics underscores the synergy between academic research and industry innovation, fostering rapid development of targeted cancer therapies. As this drug candidate progresses through clinical evaluation, it positions itself at the forefront of precision oncology focused on exploiting vulnerabilities in cancer cell signalling networks.

Subject of Research: Targeted disruption of the RAS-PI3K interaction to inhibit tumor growth in cancers driven by RAS and HER2 mutations.

Article Title: Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2

News Publication Date: 9 October 2025

Web References: http://dx.doi.org/10.1126/science.adv2684

References: Klebba, J. et al. (2025). Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2. Science. 10.1126/science.adv2684.

Keywords: Drug discovery, Tumor cells

Mammalian social structures often rely on hierarchical organization to mitigate conflict and ensure reproductive success. In mice, such hierarchies play a critical role in maintaining social order, where dominant individuals exert control over resources and mating opportunities. Prior hypotheses suggested that dominance behaviours in mice might be fixed traits, or alternatively, that visual or physical cues such as size or posture communicate rank. However, the Crick team challenged this notion by demonstrating that chemical communication is paramount for rank assessment in unfamiliar mice.

The experimental foundation of the study was built around a well-established behavioral assay involving a transparent tube confrontation. Two male mice, introduced from opposite ends of the tube, meet in the center in what becomes a contest of dominance. Traditionally, the subordinate individual retreats, cementing the dominance hierarchy. By analyzing these interactions first within cage-mates to establish a baseline hierarchy, researchers then exposed mice to unknown opponents to observe how rank recognition occurred under unfamiliar conditions.

Strikingly, mice exhibited an immediate ability to assess the dominant status of an intruder without prior direct encounters. This indicates a form of social inference, where mice compare others’ rank to their own via detected chemical signals. To disentangle which sensory modalities facilitated this recognition, experiments were conducted in complete darkness, effectively ruling out visual cues, and on castrated animals, removing the potential influence of sex hormones. Neither manipulation hindered the mice’s ability to correctly identify social rank.

The research further dissected the chemosensory systems in mice, focusing on two pivotal pathways: the olfactory system, responsible for airborne odor detection, and the vomeronasal system, which processes chemical signals transferred through direct physical contact. Blocking either system independently left rank recognition intact, suggesting a redundant or compensatory mechanism. However, simultaneous ablation of both systems abolished the ability to discern social rank, highlighting the necessity of integrated chemosensory input for accurate social judgement.

This dual-sensory reliance spotlights an elegant neural integration process, where airborne and contact-based chemical cues are synthesized to guide social decisions. The work hints at complex neural computations occurring before observable dominance or submissive behaviours manifest, implying that social rank perception is a cognitive process as much as a behavioral one. This challenges older views suggesting that certain mice are inherently aggressive or submissive, showing instead that behaviour is context-dependent and governed by sensory-driven assessment.

Beyond the realm of murine social hierarchies, this research offers compelling analogies to human social cognition. Just as mice use chemical signals to evaluate social rank, humans infer social status through a multitude of sensory inputs—including language nuances, facial expressions, and attire—allowing dynamic social navigation even in unfamiliar groups. The parallels drawn provide a fascinating perspective on how social hierarchies might be universally processed across species with distinct sensory modalities.

Neven Borak, the study’s lead author, reflects on this intersection of animal and human social processing: “Mice weigh up strangers using chemical cues and can detect social status without needing an extensive history of confrontations with those specific opponents. This is a fascinating phenomenon that humans do too mostly using visual cues. Our work offers an interesting perspective on social mobility: humans, like mice, can enter a new group of people but still maintain understanding of own social rank and gauge the social status of unfamiliar people.”

Jonny Kohl, senior author and group leader at the Francis Crick Institute’s State-Dependent Neural Processing Laboratory, emphasized the novelty of these insights: “We’ve shown for the first time how mice integrate internal and external information about dominance. This shows that a decision based on relative ranks is made in the brain before mice show either aggression or submissive behaviour, rather than there being fixed differences in behaviours leading to an aggressive or docile mouse.”

The lab’s broader research agenda focuses on how physiological states modulate neural circuits and behavior. Understanding how internal states such as stress, pregnancy, or sleep impact cognitive functions could open new vistas into the neuroscience behind social behaviour. This study into dominance rank recognition thus represents a vital step in decoding the intersection between bodily states, sensory processing, and social decision-making.

Future research will delve deeper into mapping the specific brain regions responsible for these complex computations of social rank. By pinpointing neural circuits that integrate chemical cues with internal physiological signals, scientists aim to clarify the neural architecture underpinning decision-making processes related to dominance, submission, and social interaction strategy.

This discovery underscores the essential role of chemosensation in social cognition—a sensory process often overshadowed by vision and audition in higher mammals but clearly vital in the animal kingdom. Such insights may provide foundational knowledge for addressing social behavior abnormalities in neuropsychiatric conditions and inform the development of novel therapeutic strategies.

Ultimately, the Francis Crick Institute’s study paints a rich picture of how animals navigate social landscapes through sensory integration and cognitive evaluation. The intricate dance of chemical signals guiding the subtleties of dominance and submission expands our appreciation of animal behaviour complexity and mirrors key aspects of human social intelligence.

Subject of Research: Dominance rank inference in mice using chemosensory systems

Article Title: Dominance rank inference in mice via chemosensation

News Publication Date: 19-May-2025

References: Borak, N. et al. (2025). Dominance rank inference in mice via chemosensation. Current Biology.

Keywords: Mouse models, Social hierarchy, Chemosensation, Olfactory system, Vomeronasal system, Behavioral neuroscience, Social cognition, Animal models

Malaria continues to claim over half a million lives annually, predominantly caused by P. falciparum, the deadliest of malaria parasites responsible for more than 95% of malaria mortality worldwide. Traditional treatments, although initially effective, face the constant threat of evolving parasite resistance, making it imperative to identify novel targets that can disrupt the parasite’s complex interplay with human host cells. The study, published in Nature Microbiology, sheds light on the molecular evolution and functional specificity of the FIKK kinase family, offering a promising target for next-generation antimalarial drugs.

A hallmark of P. falciparum infection is its ability to remodel host red blood cells to enhance survival and transmission. Approximately 10% of the parasite’s proteins are exported into the host cell during infection, radically altering its structure and adhesiveness to blood vessel walls and other infected cells, which can lead to severe pathological clots. Among these exported proteins, FIKK kinases stand out due to their enzymatic activity; they function as protein kinases, modifying host and parasite proteins through phosphorylation, thereby regulating essential pathways crucial for parasite survival in the human host.

By analyzing an extensive dataset of over two thousand P. falciparum genomes obtained from infected individuals, the research team uncovered strong evolutionary conservation in 18 out of 21 FIKK kinase genes. This selective preservation points to their indispensable roles in maintaining the parasite’s infectivity and hints at their contribution to the parasite’s adaptation from nonhuman primates to humans. These findings suggest that FIKK kinases have been central in the parasite’s evolutionary journey, reinforcing the hypothesis that targeting these kinases could cripple the parasite’s ability to thrive within human hosts.

To characterize their functions, each FIKK kinase was expressed recombinantly in bacterial cells, allowing detailed biochemical investigations. The experiments revealed that despite sharing structural frameworks, individual FIKK kinases exhibit distinct substrate specificities, targeting an array of host cell proteins. Remarkably, one kinase demonstrated the unprecedented ability to phosphorylate tyrosine residues in proteins, a modification not previously attributed to malaria parasites. This discovery insinuates an evolutionary refinement enabling the parasite to hijack host cell signaling pathways that rely on tyrosine phosphorylation, a mechanism widespread in mammalian cellular communication.

The molecular basis for this functional diversity was further elucidated using computational modeling and state-of-the-art protein structure prediction algorithms, including AlphaFold 2. The data pointed towards subtle yet critical variations within a flexible loop region of the kinase domain as the determinant for binding specificity. While these loop regions differ enough to diversify function, they also share conserved structural motifs that distinguish FIKK kinases from their human counterparts. This unique feature identifies them as attractive selective drug targets, minimizing potential off-target effects on human kinases.

With these insights, the team embarked on high-throughput screening of compounds known to inhibit human kinases, collaborating with pharmaceutical giant GlaxoSmithKline. This approach unveiled three molecules with promising inhibitory properties against FIKK kinases. Two of these compounds inhibited the majority of FIKK family members in vitro, highlighting the potential of designing broad-spectrum antimalarials that disable multiple kinases simultaneously. This multiplex inhibition strategy can reduce the likelihood of drug resistance, a significant hurdle in current malaria therapies.

The concept of blocking an entire kinase family rather than focusing on individual proteins represents a paradigm shift in antimalarial drug design. Moritz Treeck, head of the research laboratory at GIMM, emphasized the evolutionary context, noting that the FIKK kinase family expanded as Plasmodium parasites transitioned from infecting birds to great apes approximately one million years ago. This expansion likely facilitated adaptation to the complex physiology of mammalian hosts, culminating in P. falciparum’s recent jump to humans. Persisting reliance on these kinases underscores their viability as universal intervention points across related Plasmodium species.

Hugo Belda, co-first author of the study, highlighted the interdisciplinary nature of the research, which entailed collaborative efforts spanning molecular evolution, biochemistry, structural biology, and chemical inhibition studies. The team’s comprehensive approach produced a holistic view of P. falciparum evolutionary biology and pathogenicity. Belda also underscored the clinical implications, suggesting that compounds targeting multiple kinases simultaneously may represent a robust avenue to circumvent the rapid emergence of drug-resistant Plasmodium strains seen in single-target treatments.

Central to this research was the integration of cutting-edge technologies, including protein-protein interaction analyses, proteomics, and flow cytometry, which facilitated precise dissection of the parasite’s cellular machinery. The collaboration extended beyond the Francis Crick Institute and GIMM, encompassing international partners such as Christian Landry’s team at Université Laval in Canada. This multidisciplinary alliance exemplifies how converging expertise can accelerate translational science aimed at addressing one of humanity’s oldest scourges.

Moving forward, the research team intends to focus on refining the identified compounds for therapeutic use in humans. This includes optimizing their chemical properties to enhance bioavailability, target specificity, and safety profiles. Should these efforts succeed, they could pave the way for a new class of antimalarial drugs that strategically incapacitate the parasite’s exported kinase machinery, offering fresh hope in the global campaign against malaria.

This seminal work not only advances our understanding of parasite biology and host adaptation but also elevates the importance of targeting evolutionary conserved protein families in infectious diseases. By leveraging both evolutionary insights and structural biology, the study marks a critical step toward innovative and durable malaria treatments.

Subject of Research: Cells
Article Title: The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound
News Publication Date: 19-May-2025
Web References: http://dx.doi.org/10.1038/s41564-025-02017-4
References: Belda, H., & Bradley, D., et al. (2025). The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound. Nature Microbiology. https://doi.org/10.1038/s41564-025-02017-4
Keywords: Malaria, Plasmodium, FIKK kinases, kinase inhibitors, protein phosphorylation, drug resistance, parasitic diseases, host-pathogen interaction