ArticleOncogene2024
MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation.
Article in Oncogene, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
- Spermidine in Colorectal cancer: friend or foe?Amino acids · 2026Review
- Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer.The Journal of biological chemistry · 2026Article
- Inflammation and Colorectal Cancer Pathogenesis: Molecular, Immunological, and Environmental Features for Therapy Response and Resistances.International journal of molecular sciences · 2026Review
- Article
- From PIK3CA Mutations to Rational PI3K Inhibition for the Treatment of Colorectal Cancer.Molecular diagnosis & therapy · 2026Review
- Opposite effects of spermidine and GC7 in cell culture are dictated by distinct molecular targets.The Biochemical journal · 2025Article
- Circular RNAs modulate cancer drug resistance: advances and challenges.Cancer drug resistance (Alhambra, Calif.) · 2025Article
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Authors and funding
17 authors.
Funding
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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