CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is one of the important components of non‐small‐cell lung cancer (NSCLC) and leads to many deaths every year. During the initiation and progression of the LUAD, the Hh‐GLI2 pathway plays critical roles. Several components of this pathway have been shown to be amplified or overexpressed in LUAD, providing this pathway as an attractive target for therapeutics. However, a gap in our understanding of the Hh‐GLI2 pathway is the identity of transcriptional targets of GLI2 that drive LUAD tumorigenesis. Here, we show that the oncogene CRKL is a direct target of GLI2. GLI2 turns on CRKL transcription through binding its second intron. Furthermore, CRKL is an essential mediator for GLI2‐driven proliferation and migration of LUAD cells. Depletion of CRKL blunts Hh‐GLI2 pathway‐mediated cell proliferation and invasion. Lastly, we find that CRKL knockout cells are more sensitive to EGFR‐TKI and chemotherapeutics. Taken together, our work here identifies a specific target for Hh‐related malignancies and provides CRKL as a promising therapeutic target for LUAD.