Biology subjects

Ohh, M.

Publications and source records attributed to Ohh, M..

4 recordsLinked to original sources

bioRxiv2026

Efficacy of RMC-6236 (Daraxonrasib) and novel combination strategies targeting resistance in RAS pathway-driven neuroblastoma

Metastatic neuroblastoma (NB), the most common pediatric extra-cranial solid tumor, has a cure rate of <50%. DNA-sequencing studies have demonstrated rare recurrent driver mutations at diagnosis, with the most common alterations detected in ALK-RAS-MAPK pathway. Activating ALK and RAS-MAPK mutations are associated with inferior outcome and are increased at relapse, and thus, represent therapeutic vulnerabilities in NB. Previously, we identified combinations of RAS/MAPK inhibitors, including SHP2 and MEK, with efficacy in resistant MAPK-altered tumor cells, including those with the most common NB-associated RAS mutation NRAS-Q61K. However, toxicities of SHP2 inhibitors and promising results using compounds that directly target RAS suggest there may be superior strategies to target RAS/MAPK pathway in NB. Here, we have assessed the efficacy of RAS/MAPK inhibitors, including tovorafenib (pan-RAF), RMC-6236/daraxonrasib (pan-active-RAS) and avutometinib (RAF/MEK) in NB in vitro and in vivo using NB models harboring differing genomic status of RAS/MAPK pathway effectors. We demonstrate selective efficacy of RMC-6236 and avutometinib via RAS-MAPK pathway inhibition in NB cells and xenografts harboring RAS, NF1 or ALK alterations. Importantly, we demonstrate that presence of the NRAS-Q61K mutation confers drug sensitivity. Using newly generated and previously established NB cell models of acquired resistance to RMC-6236 or the ALK inhibitor lorlatinib, we identified targeted combinations, including RMC-6236 plus avutometinib, that demonstrate re-sensitization in resistant NB cell and xenograft models. Finally, transcriptomic studies of RMC-6236-resistant cells detected upregulation of RAS/MAPK signatures, as well as TNF/NF{kappa}B and IL-6/JAK/STAT3 pathway enrichment, thus informing future combinations to enhance sensitivity to RAS inhibitors. STATEMENT OF SIGNIFICANCEOur work demonstrates that newly available RAS pathway inhibitors RMC-6236/daraxonrasib and avutometinib have efficacy in neuroblastoma tumors, which have frequent alterations in the RAS/MAPK pathway. These drugs with early efficacy results in adult RAS-driven tumors provide an important option for patients with relapsed neuroblastoma alone or in combination.

Cancer Biology↗

bioRxiv2025

Erythrocytosis-inducing PHD2 mutations implicate biological role for N-terminal prolyl-hydroxylation in HIF1α oxygen-dependent degradation domain

Mutations in EGLN1, the gene encoding for hypoxia-inducible factor (HIF) prolyl-4-hydroxylase 2 (PHD2), cause erythrocytosis and in rare cases the development of neuroendocrine tumors. In the presence of oxygen, PHD2 hydroxylates one or both conserved prolines in the oxygen-dependent degradation domain (ODD) of HIF subunits, sufficiently marking HIF for binding and ubiquitylation via the von Hippel-Lindau (VHL) tumor suppressor protein-containing E3 ubiquitin ligase and subsequent degradation by the 26S proteasome. However, prolyl-hydroxylation in the C-terminal ODD appears to be the predominant and sufficient event in triggering the oxygen-dependent destruction of HIF, rendering the biological significance of N-terminal ODD proline unclear. Here, we examined 7 disease-associated EGLN1 mutations scattered across the catalytic core and show definitively that all PHD2 mutants have a structural and/or catalytic activity defect as measured by time-resolved nuclear magnetic resonance. Notably, we identified one of the PHD2 mutants, P317R, to retain comparably wild-type capacity to hydroxylate the predominant proline in the C-terminal ODD but had uniquely compromised ability to hydroxylate the N-terminal ODD proline. These findings support the notion that deregulation of HIF ultimately underlies PHD2-driven erythrocytosis and challenge the currently held uncertainty that the N-terminal ODD prolyl-hydroxylation event is dispensable in normal hypoxic signaling pathway.

biochemistry↗

bioRxiv2020

A cell-autonomous PD-1/PD-L1 circuit promotes tumorigenicity of thyroid cancer cells by activating a SHP2/Ras/MAPK signalling cascade

The programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2 are immune checkpoints. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their anti-cancer activity. Recently, PD-1 expression has been found in cancer cells. We analysed expression and functions of PD-1 in thyroid cancer (TC). Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 overexpression/stimulation promoted TC cell proliferation and migration in culture. PD-1 recruited the SHP2 phosphatase, potentiated its phosphatase activity thus enhancing Ras activation by dephosphorylation of inhibitory tyrosine 32 and triggering the MAPK cascade. PD-1 inhibition decreased, while PD-1 overexpression facilitated, TC cell xenograft growth by affecting cell proliferation. PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the Ras/MAPK pathway.

cancer biology↗

bioRxiv2017

Translational and HIF1α-dependent metabolic reprograming underpin oncometabolomeplasticity and synergy between oncogenic kinase inhibitors and biguanides.

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI - biguanide combinations is impeded by HIF1 and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

cancer biology↗