Synergistic RAS-MAPK and AKT Activation in MYC-Driven Tumors via Adjacent PVT1 Rearrangements

Tiwari, A.; Paithane, U.; Friedlein, J.; Tashiro, K.; Saulnier, O.; Barbosa, K. O.; Trinh, Q.; Hall, B.; Saha, S.; Soni, A.; Nakashima, T.; Bobkov, A. A.; Fujimoto, L. M.; Murad, R.; Maurya, S.; Saraswat, M.; Sarmashghi, S.; Lange, J. T.; Wu, S.; Masihi, M. B.; Ghosh, S.; Hemmati, G.; Chapman, O. S.; Hendrikse, L. D.; James, B.; Luebeck, J.-C.; Eisemann, T.; Tzaridis, T.; Rohila, D.; Leary, R.; Varshney, J.; Konety, B.; Dehm, S. M.; Kawakami, Y.; Beroukhim, R.; Largaespada, D.; Stein, L. D.; Chavez, L.; Suzuki, H.; Weiss, W. A.; Zhao, J.; Deshpande, A.; Wechsler-Reya, R. J.; Taylor, M. D.; Bag

doi:10.1101/2025.02.17.638454

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bioRxiv · 10.1101/2025.02.17.638454

Synergistic RAS-MAPK and AKT Activation in MYC-Driven Tumors via Adjacent PVT1 Rearrangements

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Abstract

MYC-driven (MYC+) cancers are aggressive and often fatal. MYC dysregulation is a key event in these cancers, but overexpression of MYC alone is not always enough to cause cancer. Plasmocytoma Variant Translocation 1 (PVT1), a long non-coding RNA (lncRNA) adjacent to MYC on chromosome 8 is a rearrangement hotspot in many MYC+ cancers. In addition to being co-amplified with MYC, the genomic rearrangement at PVT1 involves translocation, which has had obscure functional consequences. We report that translocation at the PVT1 locus cause asymmetric enrichment of 5-PVT1 and loss of 3-PVT1. Despite being classified as a non-coding RNA, the retained 5 region of PVT1 generates a circular RNA (CircPVT1) that codes for the novel peptide we call Firefox (FFX). FFX augments AKT signaling and synergistically activates MYC and mTORC1 in these cells. Further, the 3 end of PVT1, which is lost during the translocation, codes for a tumor-suppressing micropeptide we named as Honeybadger (HNB). We demonstrate that HNB interacts with KRAS and disrupts the activation of KRAS effectors. Loss of HNB leads to activation of RAS/MAPK signaling pathway, and enhances MYC stability by promoting phosphorylation of MYC at Ser62. These findings identify PVT1 as a critical node that synchronizes MYC, AKT, and RAS-MAPK activities in cancer. Our study thus identifies a key mechanism by which rearrangements at the PVT1 locus activate additional oncogenic pathways that synergize with MYC to exacerbate the aggressiveness of MYC+ cancers. This newfound understanding explains the poor prognosis associated with MYC+ cancers and offers potential therapeutic targets that could be leveraged in treatment strategies for these cancers.

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Tiwari, A., Paithane, U., Friedlein, J., Tashiro, K., Saulnier, O., Barbosa, K. O., Trinh, Q., Hall, B., Saha, S., Soni, A., Nakashima, T., Bobkov, A. A., Fujimoto, L. M., Murad, R., Maurya, S., Saraswat, M., Sarmashghi, S., Lange, J. T., Wu, S., Masihi, M. B., Ghosh, S., Hemmati, G., Chapman, O. S., Hendrikse, L. D., James, B., Luebeck, J.-C., Eisemann, T., Tzaridis, T., Rohila, D., Leary, R., Varshney, J., Konety, B., Dehm, S. M., Kawakami, Y., Beroukhim, R., Largaespada, D., Stein, L. D., Chavez, L., Suzuki, H., Weiss, W. A., Zhao, J., Deshpande, A., Wechsler-Reya, R. J., Taylor, M. D., Bag. 2025-02-22. Synergistic RAS-MAPK and AKT Activation in MYC-Driven Tumors via Adjacent PVT1 Rearrangements. https://doi.org/10.1101/2025.02.17.638454

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