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MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation

Oncogene volume 43, pages 3349–3365 (2024)Cite this article

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Abstract

The MYC oncogene is frequently overexpressed in tumors and inhibition of its translation is considered an attractive therapeutic opportunity. Despite numerous reports proposing an internal ribosome entry site (IRES) within the MYC Upstream Region (MYC UR) to sustain MYC translation during cellular stress or chemotherapy, conflicting evidence remains regarding the validity of such a mechanism. Through comprehensive investigations in MYC-driven Colorectal Cancer (CRC) and Burkitt Lymphoma (BL) cells, we demonstrate that MYC UR does not facilitate cap-independent translation, but instead orchestrates resistance to PI3K inhibitors. Genomic deletion of MYC UR neither impacts MYC protein levels nor viability in CRC cells, either untreated or exposed to cellular stress. However, in response to PI3K inhibitors, MYC UR drives a FOXO3a-dependent transcriptional upregulation of MYC, conferring drug resistance. This resistance is mediated by enhanced autophagic flux, governed by MYC, and blockade of autophagy sensitizes CRC cells to PI3K inhibition in vitro and in vivo. Remarkably, BL cells lacking the translocation of MYC UR exhibit sensitivity to PI3K inhibitors, whereas MYC UR-translocated cells respond to these drugs only when autophagy is inhibited. These findings challenge previous notions regarding IRES-mediated translation and highlight a promising strategy to overcome resistance to PI3K inhibitors in MYC-driven malignancies, offering potential clinical implications for CRC and BL treatment.

In response to BKM120, the upstream region of MYC (UR) enhances MYC expression, via FOXO3a, leading to increased autophagic flux and resistance to PI3K inhibitors (left). Pharmacological blockade of autophagy (center) or lack of translocated MYC UR along with MYC CDS in BL (right) overcome resistance and induces cells death. Image created in BioRender.

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Fig. 1: The MYC UR does not mediate IRES-dependent translation in colon cancer cells.
Fig. 2: MYC UR does not regulate MYC content or cell proliferation in response to various cell stress.
Fig. 3: MYC UR provides resistance to PI3K inhibition.
Fig. 4: PI3K inhibition enhances MYC transcription via MYC UR.
Fig. 5: Resistance of CRC cells to PI3K inhibitors is linked to MYC-mediated increase of autophagy.
Fig. 6: Autophagy blockade overcomes CRC resistance to PI3K inhibitors.
Fig. 7: Autophagic chemoresistance mediated by the MYC UR is abrogated in translocation-specific Burkitt Lymphoma cells.

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All data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Drs Pankaj Trivedi and Eleni Anastasiadou for sharing Raji and DG75 cells and advice, and Drs Cristiano Simone and Martina Lepore Signorile for providing FOXO3a expression vector and antibody. This work was funded by the Fondazione AIRC (Associazione Italiana per la Ricerca sul Cancro) IG 25833 to GC, IG20801 to LuDM, IG24329 to GG, AIRC Italy Post-Doc fellowship (to RB), MIUR PRIN 2022 2022L332YR (GC), MIUR PRIN 2022 under 40 2022J8X7PJ (SC) Sapienza University of Rome RG12117A61923A6F (GC), Institute Pasteur Italy—Fondazione Cenci Bolognetti, call 2020 “Anna Tramontano” (GC), Fondazione Umberto Veronesi fellowship (to LDM), Dipartimenti di Eccellenza 2018-2022 and 2023-2027 (L. 232/2016).

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  1. These authors contributed equally: Rosa Bordone, Devon Michael Ivy.

Authors and Affiliations

  1. Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy

    Rosa Bordone, Devon Michael Ivy, Rodrigo D’Amico, Martina Barba, Francesca Bufalieri, Alessio Balzerano, Giuseppe Giannini, Lucia Di Marcotullio, Laura Di Magno, Sonia Coni & Gianluca Canettieri

  2. Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Via Liborio Giuffrè 5, 90127, Palermo, Italy

    Miriam Gaggianesi & Giorgio Stassi

  3. McMaster University, Faculty of Health Sciences, Department of Medicine, 1200, Main St W, Hamilton, ON, Canada

    Fiorella Di Pastena

  4. Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy

    Bianca Cesaro & Alessandro Fatica

  5. Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy

    Enrico De Smaele

  6. Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy

    Gianluca Canettieri

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Contributions

GC conceived and coordinated the project, designed experiments, analyzed data and wrote the paper, RB and DMI designed and performed experiments, analyzed data, and wrote the paper, RDA, MB, FDP, BC, FB, AB, MG performed experiments and analyzed data, EDS, GG, LuDM, AF, LDM, SC, GS analyzed data and reviewed the manuscript.

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Correspondence to Gianluca Canettieri.

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All methods involving human derived materials and animal subjects were performed in accordance with the relevant local regulation and guidelines. All mouse experiments were performed according to the European Community Council Directive 2010/63/EU and carried out under the approval of the Institutional Animal Care Committee and Ministry of Health (protocol n. C1368.26). Patient-derived colorectal cancer stem cells were obtained in accordance with the ethical standards regarding Human Experimentation and informed consent was obtained from each patient in this study under Institutional Review Board protocols (authorization CE9/2015, Policlinico Paolo Giaccone, Palermo, Italy).

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Bordone, R., Ivy, D.M., D’Amico, R. et al. MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation. Oncogene 43, 3349–3365 (2024). https://doi.org/10.1038/s41388-024-03170-6

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