Oncogenic ERK signaling represses chaperone-mediated autophagy through transcriptional control of LAMP-2A

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway governed by the rate-limiting receptor LAMP-2A and increasingly implicated in cancer. However, the oncogenic circuits that enforce CMA repression and whether this state is therapeutically reversible remain unclear. Here, we developed a quantitative bioluminescence-based reporter to measure CMA activity in human cancer cells and combined parallel chemical and genome-scale CRISPR-Cas9 screens to define regulatory pathways. The chemical screen identified GSK1059615 as a CMA-restoring compound that increased LAMP-2A transcription and protein abundance in vitro and in vivo. In parallel, the CRISPR screen revealed ERK signaling as a pathway-level suppressor of CMA. Genetic or pharmacologic ERK inhibition de-repressed LAMP-2A expression, while integrated modulation of ERK, PI3K-AKT, and p38 signaling coordinated transcriptional induction and stabilization of LAMP-2A. Transcriptomic analyses further implicated FOXO1/FOXP1-driven programs in LAMP-2A regulation. Together, these findings position CMA as an integrated output of oncogenic signaling networks and establish a mechanistic framework for restoring CMA activity in defined cancer contexts.