What question did this study set out to answer?

The study aims to understand why ATRA doesn't work well in some acute myeloid leukemia and solid tumors and find ways to make it effective.

May 14, 2026Open Access

mTOR inhibition promotes ATRA-induced cancer cell differentiation by overcoming a metabolic hyperactive state

Key Points

The study aims to understand why ATRA doesn't work well in some acute myeloid leukemia and solid tumors and find ways to make it effective.
High-throughput sequencing including single-cell multiomics and RNA-seq was used.
Cell lines were treated with ATRA and the mTOR inhibitor PP242 for analysis.
Functional validation involved flow cytometry and cell line derived xenografts.
ATRA activates differentiation programs but also a hyperactive metabolic state in non-APL AML cells.
Inhibited mTOR with PP242 reduces the metabolic surge, promoting effective differentiation.
Cancers with RAS mutations showed increased responsiveness to ATRA, especially with PP242.

Abstract

BACKGROUND: All-trans retinoic acid (ATRA), a derivative of vitamin A, potently induces cell maturation in acute promyelocytic leukemia (APL). However, this therapeutic effect is attenuated or absent in non-APL acute myeloid leukemia (AML) and solid tumors. This study aims to elucidate the mechanisms underlying ATRA resistance and identify strategies to overcome it. METHODS: Integrated high-throughput sequencing-including single-cell multiomics, digital RNA with pertUrbation of genes (DRUG)-seq, bulk RNA-seq, ATAC-seq and CUT&Tag-was performed on AML and solid tumor cell lines treated with ATRA and the mTOR inhibitor PP242. Functional validation was conducted using flow cytometry, siRNA transfection, morphological assessment, Western Blotting and cell line derived xenografts (CDX). Pan-cancer analysis leveraged the Tahoe-100 M pharmacological perturbation dataset to assess metabolic responses across 50 cancer cell lines. RESULTS: ATRA simultaneously activates myeloid differentiation programs and a hyperactive metabolic state that impedes terminal maturation in non-APL AML cells. Pharmacological inhibition of the mechanistic target of the mTOR pathway with PP242 suppresses this metabolic surge and redirects transcriptional output toward effective differentiation. The Tahoe-100 M analysis reveals that cancers harboring oncogenic RAS mutations exhibit heightened metabolic responsiveness to ATRA, a vulnerability confirmed in RAS-mutant lung and colon carcinoma cell lines. In these models, ATRA and PP242 synergistically promotes cell maturation and reduces viability. CONCLUSIONS: These findings uncover a conserved metabolic barrier that limits ATRA-induced differentiation beyond APL. mTOR acts as a critical node governing the balance between pro-differentiation and pro-metabolic signals. Co-targeting mTOR overcomes this barrier, particularly in RAS-mutant malignancies, providing a genotype-informed rationale for extending differentiation therapy to broader cancer contexts.

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