CircCAMSAP1 promotes osimertinib resistance in NSCLC by stabilizing HSPA1A through inhibition of SMURF1-mediated ubiquitination

Osimertinib resistance is a key obstacle to the long-term efficacy of epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer (NSCLC). This study identified circCAMSAP1 (hsa_circ_0001900), a circular RNA (circRNA), as a key driver of acquired resistance. Functionally, circCAMSAP1 promotes proliferation, migration, invasion, and drug resistance in vitro and tumor growth in vivo. CircCAMSAP1 is upregulated in drug-resistant NSCLC cells and promotes cell survival by enhancing autophagic flux. Mechanistically, circCAMSAP1 prevents ubiquitination and proteasomal degradation of HSPA1A by disrupting the interaction between heat shock protein family A (Hsp70) member 1A (HSPA1A) and Smad-specific E3 ubiquitin protein ligase 1 (SMURF1). HSPA1A, a member of the HSP70 family, restores osimertinib sensitivity by targeting HSPA1A in vitro and in vivo by its allosteric inhibitor, JG-231. In addition, we found that the RNA-binding protein HnRNPA1 promotes the biogenesis of circCAMSAP1 by recognizing intron flanking motifs. Our study reveals a previously unrecognized mechanism of drug resistance involving circRNA-mediated regulation of protein homeostasis targeting the HnRNPA1/circCAMSAP1/SMURF1/HSPA1A axis, elucidating the mechanism of action of circCAMSAP1 in NSCLC tumorigenesis and EGFR-TKI resistance, providing a new target for NSCLC resistance therapy.