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Serine/threonine-protein kinase B-raf (BRAF) mutations are found in 8-15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF-mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF-mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune-mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic-damage-associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF-mutant murine tumors and mobilized the danger-signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug-treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3) + T-cell surface glycoprotein CD4 (CD4) + T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF-mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF-mutant colorectal cancer patients., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF V600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF V600E has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC 50 values in the 40-88 nM range. Selected compounds inhibited BRAF V600E signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11 , the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.

Macrophages are main players of the innate immune system. They show great heterogeneity and play diverse functions that include support to development, sustenance of tissue homeostasis and defense against infections. Dysfunctional macrophages have been described in multiple pathologies including cancer. Indeed tumor-associated macrophages (TAMs) are abundant in most tumors and sustain cancer growth, promote invasion and mediate immune evasion. Importantly, lipid metabolism influences macrophage activation and lipid accumulation confers pathogenic features on macrophages. Notably, a subset of lipid-loaded macrophages has been recently identified in many tumor types. Lipid-loaded TAMs support tumor growth and progression and exert immune-suppressive activities. In this review, we describe the role of lipid metabolism in macrophage activation in physiology and pathology and we discuss the impact of lipid accumulation in macrophages in the context of cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tumor-associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa). The mechanistic basis of this correlation and therapeutic strategies to target TAMs in PCa remain poorly defined. Here, single-cell RNA sequencing was used to profile the transcriptional landscape of TAMs in human PCa, leading to identification of a subset of macrophages characterized by dysregulation in transcriptional pathways associated with lipid metabolism. This subset of TAMs correlates positively with PCa progression and shorter disease-free survival and is characterized by an accumulation of lipids that is dependent on Marco. Mechanistically, cancer cell-derived IL-1β enhances Marco expression on macrophages, and reciprocally, cancer cell migration is promoted by CCL6 released by lipid-loaded TAMs. Moreover, administration of a high-fat diet to tumor-bearing mice raises the abundance of lipid-loaded TAMs. Finally, targeting lipid accumulation by Marco blockade hinders tumor growth and invasiveness and improves the efficacy of chemotherapy in models of PCa, pointing to combinatorial strategies that may influence patient outcomes., Competing Interests: Disclosures: R.A. DePinho reported being a Founder and Advisor for Tvardi Therapeutics, Asylia Therapeutics, Nirogy Therapeutics, Stellanova Therapeutics, and Sporos Bioventures. The focus of these companies is not directly related to the content of this manuscript. S. Gordon reported personal fees from Verseau, Myeloid Therapeutics, and Alnylam outside the submitted work. No other disclosures were reported., (© 2021 Masetti et al.)

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one] is a new, nonselective, and reversible monoamine oxidase (MAO) inhibitor, belonging to a oxazoloquinolinone series. In vitro studies showed that SL25.1131 inhibits rat brain MAO-A and MAO-B with IC50 values of 6.7 and 16.8 nM and substrate-dependent Ki values of 3.3 and 4.2 nM, respectively. In ex vivo conditions, the oral administration of SL25.1131 induced a dose-dependent inhibition of MAO-A and MAO-B activities in the rat brain with ED50 values of 0.67 and 0.52 mg/kg, respectively. In the rat brain, duodenum, and liver, the inhibition of MAO-A and MAO-B by SL25.1131 (3.5 mg/kg p.o.) was reversible, and the recovery of MAO-A and MAO-B activities was complete 16 h after administration. SL25.1131 (3.5 mg/kg p.o.) increased tissue levels of dopamine (DA), norepinephrine, and 5-hydroxytryptamine and decreased levels of their deaminated metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid. In mice, SL25.1131 induced a dose-dependent potentiation of 5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypies with ED50 values of 0.60 and 2.8 mg/kg p.o., respectively. SL25.1131 was able to reestablish normal striatal dopaminergic tone and locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice. In addition, when coadministered with L-DOPA, SL25.1131 increased the available DA in the striatum and the duration of L-DOPA-induced hyperactivity. The duration of the effect of L-DOPA on circling behavior in 6-hydroxydopamine-lesioned rats was also increased. The neurochemical profile of SL25.1131 demonstrates that this compound is a mixed, potent, and reversible MAO-A/B inhibitor in vitro, in vivo, and ex vivo. SL25.1131 has therapeutic potential as a symptomatic treatment during the early phase of Parkinson's disease and as an adjunct to L-DOPA therapy during the early and late phases of the disease.