Targeting the Golgi Secretory Pathway in Chromosome 3q-amplified Human Cancer

-ABSTRACT In contrast to the advancements made in non-small cell lung cancers (NSCLC) harboring actionable mutations in KRAS or receptor tyrosine kinases, few targeted therapies are available for NSCLCs lacking these mutations. A chromosome 3q (3q) region that is frequently amplified in NSCLC and other tumor types encodes several Golgi-resident proteins, including Golgi Integral Membrane Protein 4 (GOLIM4), which encodes a manganese (Mn)-binding Golgi scaffolding protein, and ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1), which encodes a Golgi-localized Ca2+/Mn2+ ion channel that mediates Ca2+-dependent cargo sorting and secretion. We found that the 3q amplicon plays a fundamental role in NSCLC progression owing to a Golgi-dependent secretory program activated by GOLIM4 and ATP2C1. Importantly, we show that Mn causes GOLIM4 degradation, thereby inducing a secretory blockade that leads to apoptosis of 3q-amplified, but not -diploid, NSCLC cells, suggesting that the 3q amplicon creates an addiction to the Golgi-dependent secretory program. In the proposed work, we will explore how a 3q amplicon activates secretory vesicle biogenesis in the Golgi to drive NSCLC progression, and we will carry out preclinical and mechanistic studies to elucidate how Mn selectively targets 3q-amplified NSCLC. Our studies will link somatic mutagenesis to a secretory process that drives NSCLC progression and will provide a molecular basis for future clinical studies of a metal as a targeted therapy in a genetically defined NSCLC subset. Project Number: 1R01CA295608-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Xiaochao Tan | Institution: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON, HOUSTON, TX | Award Amount: $388,546 | Activity Code: R01 | Study Section: Cancer Cell Biology Study Section[CCB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293988