PLD1-driven oncogenic secretion creates a therapeutic vulnerability in chromosome 3q-amplified NSCLC

Chromosome 3q (3q) amplification is a frequent event in non-small cell lung cancer (NSCLC) and other cancer types, yet therapeutic strategies targeting oncogenic drivers within this amplicon have been unsuccessful. Our study revealed that the 3q amplicon encodes multiple Golgi-related proteins, including Phospholipase D1 (PLD1), which catalyzes the production of a potential oncogenic lipid, phosphatidic acid. We found that PLD1 is highly expressed in 3q-amplified NSCLC (3q-NSCLC) and its enzymatic activity is further boosted by coamplified PLD1 activator, ARF-like GTPase 14. High PLD1 activity is essential for 3q-NSCLC growth and metastasis. Mechanistically, PLD1 drives secretion of oncogenic factors via the carriers from the trans Golgi network to the cell surface pathway to support tumor growth. Transferrin receptor 1 (TFRC), which encodes a membrane protein, is coamplified with PLD1 and overexpressed in 3q-NSCLC. A TFRC antibody-drug conjugate (ADC) carrying a PLD1 inhibitor exhibited potential antitumor activity in mouse models. These findings establish PLD1 as a promoter of 3q-NSCLC and provide proof of concept for the development of PLD1-targeted therapies, including ADC-based approaches, for this challenging cancer subtype.