Turning off this ‘cellular switch’ could be key for NSCLC treatment

Blocking the transcription factor cAMP response element–binding protein (CREB)—a “cellular switch” that triggers tumor growth—could serve as a new drug target in hard-to-treat non-small cell lung cancer (NSCLC), according to the results of a mechanistic study published in Science Advances.

“A drug that blocks this switch could have therapeutic benefits for patients with [NSCLC],” said senior author Marc Montminy, MD, PhD, professor, Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA. “This disease has eluded efforts to identify effective treatments.

Added co-author Reuben J. Shaw, PhD, professor, Department of Molecular and Cell Biology, Salk Institute for Biological Studies: “There's really no good treatment, so any insight that helps this subset of patients is a major advance.”

The family of cAMP–regulated transcriptional coactivators (CRTCs) hooks up with CREB to promote cellular gene expression. As can be expected from its central position downstream of various growth factor signaling pathways, CREB plays a role in the survival, growth, and differentiation of both normal and cancerous cells. Increases in CREB activity have been linked to tumor progression, chemotherapy resistance, and higher mortality.

CRTCs (CRTC1, CRTC2, and CRTC3) are, for the most part, phosphorylated by a family of three salt-inducible kinases (SIKs)—SIK1, SIK2, and SIK3—and sequestered in the cytoplasm via phosphorylation-dependent interactions with 14-3-3 proteins.

Exposure to cAMP induces the protein kinase A (PKA)–mediated phosphorylation of CREB at Ser¹³³, and facilitates its association with the histone acetyltransferase paralogs CBP (CREB-binding protein) and P300. At the same time, PKA directly phosphorylates and obstructs the SIK kinases, resulting in dephosphorylation of the CRTCs, which travel to the nucleus, bind to CREB, and stimulate transcription.

SIKs and other members of the AMP-activated protein kinase family are mostly activated by the LKB1 tumor suppressor, which is the major upstream kinase. The loss of LKB1 inactivates the SIKs, thus resulting in the transportation of the CRTCs into the nucleus and the up-regulation of CREB target genes. In about 20% of NSCLC cases, LKB1 is mutationally inactivated. Furthermore, in previous mouse models, LKB1 loss was shown to play an essential role in the promotion of lung cancer. However, the role of CRTCs in NSCLC remains to be elucidated.

“Although targeted therapeutics have made substantial advances in subsets of NSCLC, therapeutic options for LKB1-mutant tumors remain limited,” wrote Drs. Montminy and Shaw and colleagues. “Because LKB1 functional loss can be caused by multiple mechanisms, including somatic gene mutations, epigenetic silencing, or posttranslational modifications, the identification of more robust biomarkers appears critical for the early detection of LKB1-deficient lung cancers.”

In the current study, Drs. Montminy and Shaw and fellow researchers identified CRTC2 as a key regulator of LKB1-deficient NSCLC, showing that CRTC2 promotes NSCLC by stimulating the expression of the inhibitor of DNA binding 1—a novel CRTC2/CREB target gene, which is up-regulated in LKB1-deficient NSCLC. In the aggregate, the authors have demonstrated the importance of the CREB/CRTC2 pathway in tying the loss of LKB1 activity in NSCLC with tumor development.

“It was an exciting finding to show how CREB ultimately contributes to this deadly type of cancer,” stated Laura Rodón, postdoctoral researcher, Peptide Biology Laboratories, Salk Institute for Biological Studies. “This gives weight to the idea that if we were able to turn off that CREB switch, we'd be able to help patients.”