WCLC 2025 - Posters & ePosters-P3.03.50 cIRCCAMSAP1 Induce Osimertinib Resistance in Lung Adenocarcinoma by Downregulating the Degradation Level of HSPA1A

P3.03.50 cIRCCAMSAP1 Induce Osimertinib Resistance in Lung Adenocarcinoma by Downregulating the Degradation Level of HSPA1A

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This study investigates the role of the circular RNA circCAMSAP1 in osimertinib resistance in lung adenocarcinoma, particularly non-small cell lung cancer (NSCLC). Using high-throughput sequencing, circCAMSAP1 was found significantly upregulated in osimertinib-resistant NSCLC cell lines (PC9/OR and H1975/OR) compared to parental cells. Molecular analyses confirmed the circular structure, expression, and cytoplasmic localization of circCAMSAP1.<br /><br />Functional assays showed that silencing circCAMSAP1 reduced proliferation, invasion, migration, and colony formation abilities of osimertinib-resistant cells, indicating its role in promoting drug resistance. RNA pulldown assays coupled with mass spectrometry identified the heat shock protein HSPA1A as interacting with circCAMSAP1, which was further confirmed by RNA immunoprecipitation.<br /><br />Mechanistically, circCAMSAP1 promotes osimertinib resistance by regulating HSPA1A protein stability. Silencing circCAMSAP1 decreased HSPA1A protein levels without affecting its mRNA expression, suggesting post-translational regulation. Proteasome inhibitor and cycloheximide chase assays revealed that circCAMSAP1 inhibits proteasomal degradation of HSPA1A. Further, circCAMSAP1 suppresses the ubiquitination of HSPA1A mediated by the E3 ubiquitin ligase SMURF1. Co-immunoprecipitation confirmed the interaction between SMURF1 and HSPA1A, and silencing circCAMSAP1 enhanced SMURF1 protein levels, promoting HSPA1A degradation.<br /><br />In vivo, knockdown of circCAMSAP1 in osimertinib-resistant cells implanted in nude mice led to reduced tumor growth and increased sensitivity to osimertinib treatment, along with altered expression of proliferation marker Ki-67 and HSPA1A in tumor tissues.<br /><br />In conclusion, circCAMSAP1 contributes to osimertinib resistance in lung adenocarcinoma by recruiting SMURF1 to inhibit ubiquitination and degradation of HSPA1A, thereby stabilizing this protein and promoting cancer cell survival. Targeting circCAMSAP1 may represent a potential strategy to overcome osimertinib resistance in NSCLC.

Asset Subtitle

Wenmei Su

Meta Tag

Speaker Wenmei Su

Topic Tumor Biology – Translational Biology

Keywords

circCAMSAP1

osimertinib resistance

lung adenocarcinoma

non-small cell lung cancer

HSPA1A

SMURF1

ubiquitination

proteasomal degradation

RNA pulldown

drug resistance