Medina, P. M. B. | Search bioRxiv

bioRxiv2026

Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression

Bohring-Opitz syndrome (BOS, OMIM#605309) is a rare neurodevelopmental disorder caused by heterozygous and truncating variants in ASXL1 (Additional Sex Combs Like 1), a chromatin-associated epigenetic regulator that forms the catalytic PR-DUB complex with BAP1. Truncating ASXL1 variants are also recurrent somatic drivers in myeloid leukemia, yet the metabolic consequences of these mutations remain undefined. Using patient derived dermal fibroblasts, we show that truncating ASXL1 variants drive a Warburg-like metabolic state characterized by increased glycolytic flux, and accumulation of pyruvate and lactate. Truncated ASXL1 and BAP1 show aberrant co-occupancy at an H3K4me3-marked intronic regulatory element within MPC2 intron 1, with broadened ASXL1 occupancy extending beyond BRD4-defined regulatory boundaries while BRD4 positioning remains unchanged, consistent with aberrant PR-DUB complex spreading beyond its normally constrained chromatin territory. This altered occupancy is accompanied by modest but significant reduction in MPC2 transcript abundance and a disproportionately larger reduction in MPC1 and MPC2 protein levels, indicating that transcriptional dysregulation at this intronic element is amplified at the protein level through post-transcriptional mechanisms including impaired MPC1/MPC2 heterodimer stability. Pharmacologic MPC inhibition recapitulates both the metabolic and Wnt signaling phenotypes of BOS cells, while canonical Wnt activation increases glycolytic flux without reducing MPC abundance, establishing mitochondrial pyruvate restriction as causally upstream of signaling dysregulation. These findings define a previously unrecognized chromatin-to-metabolism axis connecting gain-of-function ASXL1 truncation to mitochondrial pyruvate transport, identifying MPC as a central mediator of epigenetic-metabolic crosstalk in both a rare developmental syndrome and ASXL1-mutant myeloid malignancy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/737346v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1d6ee4org.highwire.dtl.DTLVardef@5b6e15org.highwire.dtl.DTLVardef@9849cforg.highwire.dtl.DTLVardef@15ebb5_HPS_FORMAT_FIGEXP M_FIG C_FIG Truncating and heterozygous ASXL1 variants cause a neurodevelopmental syndrome called Bohring-Opitz syndrome. (1) At an epigenetic level, we have shown that Truncating ASXL1 variants drive more open chromatin and aberrant activation of key developmental pathways. (2) Truncating ASXL1 mutations are sufficient to drive Decreased MPC1 and MPC2 protein levels. (3) Decreased MPC1 or MPC2 level or function are sufficient to drive increased glycolysis which is observed in BOS cells. (4) Truncating ASXL1 mutations drive Increased Wnt signaling via MPC depletion. * Increased Wnt signaling (4) is also sufficient to drive increased glycolysis (3), however Increased Wnt signaling does not drive Decreased MPC1 and MPC2 levels (2).

genetics↗

bioRxiv2025

MRTX1133 is a potent non-covalent KRAS (G12C) inhibitor with tissue-specific activity

KRAS is a high-value therapeutic target for the treatment of cancer. Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), have received accelerated approvals for clinical use. Studies of these inhibitors ushered in the development of new inhibitors such as MRTX1133, that had entered clinical trials as a KRAS (G12D)-selective, non-covalent inhibitor. However, the subsequent failure of sotorasib as monotherapy and the recent termination of an early-phase clinical trial for MRTX1133 indicates that developing clinically effective allele-specific KRAS inhibitors remains a challenge, and that there is a need for further evaluation of KRAS inhibition mechanisms. Here, we show that the reportedly KRAS (G12D)-selective MRTX1133 also binds to G12C mutant KRAS with high affinity and suppresses MAPK signaling in cancer cell lines harboring KRAS (G12C). Intriguingly, its effect on the proliferation of KRAS (G12C) cancer cells is context-dependent; MRTX1133 robustly inhibits the proliferation of the pancreatic cancer cell line MIA PaCa-2 as well as the tumor growth of MIA PaCa-2 mouse xenografts, but it has little effect in lung cancer cells. These findings, together with similar other recent reports, question if allele-specific KRAS inhibitors are truly selective and highlight the need for strategies that take into account tissue and context-specific processes. Significance StatementMRTX1133 is a reportedly selective, non-covalent inhibitor for the KRAS oncogene with a glycine-to-aspartate (G12D) mutation that is present in about 40% of pancreatic cancers. Despite the overwhelming preclinical success, the early-phase clinical trial of MRTX1133 was recently terminated with undisclosed results. Through our in vitro and in vivo studies, we discovered that MRTX1133 is also a potent non-covalent inhibitor of a glycine-to-cysteine (G12C) KRAS mutation that works in pancreatic cancer but not in lung cancer models. Our findings are consistent with other recent reports on the activity of MRTX1133 in non-G12D mutants and highlight challenges in developing true allele-specific KRAS inhibitors via non-covalent mechanisms while also accounting for tissue-specific effects.

cancer biology↗