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Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.

When molecular dimers, crystalline films or molecular aggregates absorb a photon to produce a singlet exciton, spin-allowed singlet fission may produce two triplet excitons that can be used to generate two electron–hole pairs, leading to a predicted ∼50% enhancement in maximum solar cell performance. The singlet fission mechanism is still not well understood. Here we report on the use of time-resolved optical and electron paramagnetic resonance spectroscopy to probe singlet fission in a pentacene dimer linked by a non-conjugated spacer. We observe the key intermediates in the singlet fission process, including the formation and decay of a quintet state that precedes formation of the pentacene triplet excitons. Using these combined data, we develop a single kinetic model that describes the data over seven temporal orders of magnitude both at room and cryogenic temperatures., Singlet fission is an important process occurring in solar cells, however the mechanism is not well understood. Here the authors reveal intermediates during singlet fission of a non-conjugated pentacene dimer, developing a single kinetic model to describe the data over seven temporal orders of magnitude at room and cryogenic temperatures.

Biological photosynthetic machinery allosterically regulate light harvesting via conformational and electronic changes at the antenna protein complexes as a response to specific chemical inputs. Fundamental limitations in current approaches to regulating inorganic light-harvesting mimics prevent their use in catalysis. Here we show that a light-harvesting antenna/reaction centre mimic can be regulated by utilizing a coordination framework incorporating antenna hemilabile ligands and assembled via a high-yielding, modular approach. As in nature, allosteric regulation is afforded by coupling the conformational changes to the disruptions in the electrochemical landscape of the framework upon recognition of specific coordinating analytes. The hemilabile ligands enable switching using remarkably mild and redox-inactive inputs, allowing one to regulate the photoredox catalytic activity of the photosynthetic mimic reversibly and in situ. Thus, we demonstrate that bioinspired regulatory mechanisms can be applied to inorganic light-harvesting arrays displaying switchable catalytic properties and with potential uses in solar energy conversion and photonic devices., Photosynthetic systems regulate light harvesting via structural and electronic control of antenna proteins. Here, the authors report a light-harvesting antenna/reaction centre mimic that can be allosterically regulated using mild and redox-inactive inputs, via a coordination framework with hemilabile ligands.