Cheng, M. L. | Search bioRxiv

bioRxiv2025

Multi-selective RAS(ON) Inhibition Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 and BCL2 Inhibitors in Acute Myeloid Leukemia

Aberrant activation of the RAS/MAPK signaling limits the clinical efficacy of several targeted therapies in acute myeloid leukemia (AML). In FLT3-mutant AML, the selection of clones harboring heterogeneous RAS mutations drives resistance to FLT3 inhibitors (FLT3i). RAS activation is also associated with resistance to other AML targeted therapies, including the BCL2 inhibitor venetoclax. Despite the critical need to inhibit RAS/MAPK signaling in AML, no targeted therapies have demonstrated clinical benefit in RAS-driven AML. To address this unmet need, we investigated the preclinical activity of RMC-7977, a multi-selective inhibitor of GTP-bound active [RAS(ON)] isoforms of mutant and wild-type RAS in AML models. RMC-7977 exhibited potent antiproliferative and pro-apoptotic activity across AML cell lines with MAPK-activating signaling mutations. In cell line models with acquired FLT3i resistance due to secondary RAS mutations, treatment with RMC-7977 restored sensitivity to FLT3i. Similarly, RMC-7977 effectively reversed resistance to venetoclax in RAS-addicted cell line models with both RAS wild-type and mutant genetic backgrounds. In murine patient-derived xenograft models of RAS-mutant AML, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination with gilteritinib or venetoclax. Our findings strongly support clinical investigation of broad-spectrum RAS(ON) inhibition in AML to treat and potentially prevent drug resistance due to activated RAS signaling.

cancer biology↗

bioRxiv2023

A modular circuit architecture coordinates the diversification of courtship strategies in Drosophila

Identifying a mate is a central imperative for males of most species but poses the challenge of distinguishing a suitable partner from an array of potential male competitors or females of related species. Mate recognition systems are thus subject to strong selective pressures, driving the rapid coevolution of female sensory cues and male sensory preferences. Here we leverage the rapid evolution of female pheromones across the Drosophila genus to gain insight into how males coordinately adapt their detection and interpretation of these chemical cues to hone their mating strategies. While in some Drosophila species females produce unique pheromones that act to attract and arouse their conspecific males, the pheromones of most species are sexually monomorphic such that females possess no distinguishing chemosensory signatures that males can use for mate recognition. By comparing several close and distantly-related Drosophila species, we reveal that D. yakuba males have evolved the distinct ability to use a sexually-monomorphic pheromone, 7-tricosene (7-T), as an excitatory cue to promote courtship, a sensory innovation that enables D. yakuba males to court in the dark thereby expanding their reproductive opportunities. To gain insight into the neural adaptations that enable 7-T to act as an excitatory cue, we compared the functional properties of two key nodes within the pheromone circuits of D. yakuba and a subset of its closest relatives. We show that the instructive role of 7-T in D. yakuba arises from concurrent peripheral and central circuit changes: a distinct subpopulation of sensory neurons has acquired sensitivity to 7-T which in turn selectively signals to a distinct subset of P1 neurons in the central brain that trigger courtship behaviors. Such a modular circuit organization, in which different sensory inputs can independently couple to multiple parallel courtship control nodes, may facilitate the evolution of mate recognition systems by allowing males to take advantage of novel sensory modalities to become aroused. Together, our findings suggest how peripheral and central circuit adaptations can be flexibly linked to underlie the rapid evolution of mate recognition and courtship strategies across species.

neuroscience↗