Maximilian Kramer‐Drauberg

University of Turin

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Chiara Ambrogio

University of Turin

Enrico Patrucco

University of Turin

E. Petrini

University of Turin

David Santamarı́a

Centro de Investigación del Cáncer

Zhiwei Zhou

Sichuan University

Aleksandra Bożyk

Medical University of Lublin

Giovanna Carrà

University of Turin

Xiaolu Zhang

Shandong University

Magda Bienko

Karolinska Institutet

Rossella Scardaci

University of Turin

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University of Turin

Universidad de Salamanca

Centro de Investigación del Cáncer

Medical University of Lublin

Gdańsk Medical University

McGill University

Karolinska Institutet

Centro de Investigación Biomédica en Red de Cáncer

Consejo Superior de Investigaciones Científicas

Science for Life Laboratory

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Author response for "Oncogenic mutant <scp>KRAS</scp> inhibition through oxidation at cysteine 118"

Maximilian Kramer‐Drauberg E. Petrini Alessia Mira Enrico Patrucco Rossella Scardaci

10.1002/1878-0261.13798/v2/response1

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Stimulation of RAS-dependent ROS signaling extends longevity by modulating a developmental program of global gene expression

Science Advances (2022)

Robyn Branicky Ying Wang Arman Khaki Ju‐Ling Liu Maximilian Kramer‐Drauberg

We show that elevation of mitochondrial superoxide generation increases Caenorhabditis elegans life span by enhancing a RAS-dependent ROS (reactive oxygen species) signaling pathway (RDRS) that controls the expression of half of the genome as well as animal composition and physiology. RDRS stimulation mimics a program of change in gene expression that is normally observed at the end of postembryonic development. We further show that RDRS is regulated by negative feedback from the superoxide dismutase 1 (SOD-1)-dependent conversion of superoxide into cytoplasmic hydrogen peroxide, which, in turn, acts on a redox-sensitive cysteine (C118) of RAS. Preventing C118 oxidation by replacement with serine, or mimicking oxidation by replacement with aspartic acid, leads to opposite changes in the expression of the same large set of genes that is affected when RDRS is stimulated by mitochondrial superoxide. The identities of these genes suggest that stimulation of the pathway extends life span by boosting turnover and repair while moderating damage from metabolic activity.

10.1126/sciadv.adc9851

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Pharmacological SOS1 inhibitor BI-3406 demonstrates in vivo anti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumors

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Fernando C. Baltanás Maximilian Kramer‐Drauberg Rósula García‐Navas Enrico Patrucco E. Petrini

Resistance to KRASmut inhibitors frequently arises, warranting further searches for anti-RAS cancer therapies. We evaluated the tolerability and efficacy of SOS1 pharmacological inhibition in comparison to genetic ablation in different KRAS-dependent tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. In BI-3406-treated KRASmut MEFs, we observed significantly reduced RAS-GTP levels and RAS downstream signaling, as well as decreased tumor burden and slower disease progression resulting from tumor-intrinsic and extrinsic therapeutic drug effects. In vivo analyses of KRASG12D allografts in immunocompromised mice and KRASG12D-driven lung adenocarcinomas in immunocompetent mice showed that systemic BI-3406 treatment impaired tumor growth and downmodulated components of the tumor microenvironment comparably to the KRASG12D inhibitor MRTX1133. Markedly stronger synergistic antitumor effects were observed upon concomitant BI-3406+MRTX113 treatment, confirming SOS1 as an actionable therapy target in RAS-dependent cancers.

10.1101/2024.09.18.613686

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Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

Molecular Oncology (2025)

Maximilian Kramer‐Drauberg E. Petrini Alessia Mira Enrico Patrucco Rossella Scardaci

10.1002/1878-0261.13798

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Comparative genomic profiling identifies targetable brain metastasis drivers in non-small cell lung cancer

Research Square (Research Square) (2022)

Marcin Nicoś Luuk Harbers Enrico Patrucco Maximilian Kramer‐Drauberg Xiaolu Zhang

Abstract Brain metastases (BM) severely impact the prognosis and quality of life of patients with non-small cell lung cancer (NSCLC). To identify targetable drivers of NSCLC-BM, we profiled somatic copy number alterations (SCNAs) in 51 matched pairs of primary NSCLC and BM samples from 33 patients with lung adenocarcinoma (LUAD) and 18 patients with lung squamous cell carcinoma (LUSC). BM consistently had a higher burden of SCNAs compared to the matched primary tumors, and SCNAs were typically homogeneously distributed within BM, as revealed by multi-region SCNA profiling in 15 BM samples, suggesting that BM do not undergo extensive evolution once formed. By comparing focal SCNAs in matched NSCLC-BM pairs, we identified BM driving alterations affecting multiple cancer genes, including several targetable genes such as CDK12, DDR2, ERBB2, and NTRK1, which we validated in an independent cohort of 84 BM samples. We explored the metastatic potential of CDK12 and DDR2 in vitro and in vivo and found that overexpression of either gene alone in murine lung cancer cells causes the induction of key genes involved in epithelial-mesenchymal transition. Finally, we performed whole-exome sequencing of 40 NSCLC-BM pairs and identified BM driver mutations in multiple cancer genes, including several genes involved in epigenome editing and 3D genome organization, such as EP300, CTCF, and STAG2, which we validated by targeted sequencing of an independent cohort of 115 BM samples. Our study represents the most comprehensive genomic characterization of LUAD and LUSC BM available to date, uncovering potentially targetable NSCLC-BM drivers and inspiring the design of novel precision treatment strategies for NSCLC patients.

10.21203/rs.3.rs-1320380/v1

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ROS regulation of RAS and vulva development in Caenorhabditis elegans

PLoS Genetics (2020)

Maximilian Kramer‐Drauberg Ju‐Ling Liu David Desjardins Ying Wang Robyn Branicky

Reactive oxygen species (ROS) are signalling molecules whose study in intact organisms has been hampered by their potential toxicity. This has prevented a full understanding of their role in organismal processes such as development, aging and disease. In Caenorhabditis elegans, the development of the vulva is regulated by a signalling cascade that includes LET-60ras (homologue of mammalian Ras), MPK-1 (ERK1/2) and LIN-1 (an ETS transcription factor). We show that both mitochondrial and cytoplasmic ROS act on a gain-of-function (gf) mutant of the LET-60ras protein through a redox-sensitive cysteine (C118) previously identified in mammals. We show that the prooxidant paraquat as well as isp-1, nuo-6 and sod-2 mutants, which increase mitochondrial ROS, inhibit the activity of LET-60rasgf on vulval development. In contrast, the antioxidant NAC and loss of sod-1, both of which decrease cytoplasmic H202, enhance the activity of LET-60rasgf. CRISPR replacement of C118 with a non-oxidizable serine (C118S) stimulates LET-60rasgf activity, whereas replacement of C118 with aspartate (C118D), which mimics a strongly oxidised cysteine, inhibits LET-60rasgf. These data strongly suggest that C118 is oxidized by cytoplasmic H202 generated from dismutation of mitochondrial and/or cytoplasmic superoxide, and that this oxidation inhibits LET-60ras. This contrasts with results in cultured mammalian cells where it is mostly nitric oxide, which is not found in worms, that oxidizes C118 and activates Ras. Interestingly, PQ, NAC and the C118S mutation do not act on the phosphorylation of MPK-1, suggesting that oxidation of LET-60ras acts on an as yet uncharacterized MPK-1-independent pathway. We also show that elevated cytoplasmic superoxide promotes vulva formation independently of C118 of LET-60ras and downstream of LIN-1. Finally, we uncover a role for the NADPH oxidases (BLI-3 and DUOX-2) and their redox-sensitive activator CED-10rac in stimulating vulva development. Thus, there are at least three genetically separable pathways by which ROS regulates vulval development.

Mitochondrial ROS

10.1371/journal.pgen.1008838

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Citations (17)

Discoveries in the redox regulation of KRAS

The International Journal of Biochemistry & Cell Biology (2020)

Maximilian Kramer‐Drauberg Chiara Ambrogio

10.1016/j.biocel.2020.105901

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Citations (4)

Genomic Profiling Identifies Putative Pathogenic Alterations in NSCLC Brain Metastases

JTO Clinical and Research Reports (2022)

Marcin Nicoś Luuk Harbers Enrico Patrucco Maximilian Kramer‐Drauberg Xiaolu Zhang

Epigenome

10.1016/j.jtocrr.2022.100435

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Citations (4)