Mechanistic Study of TTF-1 Modulation of Cellular Sensitivity to Cisplatin

Abstract

The lung lineage master regulator gene, Thyroid Transcription Factor-1 (TTF-1, also known as NKX2-1), is used as a marker by pathologists to identify lung adenocarcinomas since TTF-1 is expressed in 60 ~ 70% of lung ADs. Much research has been conducted to investigate roles of TTF-1 in lung cancer biology. But, how it modulates cellular chemosensitivity remains poorly characterized. Our study shows that TTF-1 sensitizes the KRAS- mutated A549 and NCI-H460 lung cancer cells to cisplatin, a common chemotherapy used to treat lung cancer. This chemosensitization activity does not appear to be mediated by a TTF-1-imposed alteration on nucleotide excision repair. Mechanistically, TTF-1 induced a reduction in p-AKT (S473), which in turn activated glycogen synthase kinase 3 (GSK3) and reduced β-catenin. Intriguingly, in the EGFR -mutated NCI-H1975 and HCC827 cells, TTF-1 desensitized these cells to cisplatin; concomitantly, TTF-1 conferred an increase in p-AKT. Finally, the conditioned media of TTF-1 -transefected cells sensitized TTF-1 − cells to cisplatin, implicating that the TTF-1 -driven chemosensitization activity may be dually pronged in both intracellular and extracellular compartments. In short, this study highlights the enigmatic activities of TTF-1 in lung cancer, and calls for future research to optimally manage chemotherapy of patients with TTF-1 + lung ADs.

The Prognostic Value of TTF-1/NKX2-1 in Lung Squamous Cell Carcinoma

“…4,13 Despite its role as a "lineage-survival" oncogene in lung ADC, it has become apparent that TTF-1 expression is associated with a favorable prognosis in NSCLC, and some recent research found TTF-1 can modulate the sensitivity to cisplatin and connect with mutated EGFR, TTF-1 positive patients also display more favorable factors like actionable target mutation. [19][20][21][22] As more signaling partners of NKX2-1 are revealed, there will be opportunities to initiate translational research for creating and developing NKX2-1-dependent strategies as tools for managing NKX2-1-positive lung cancer. The limitations in our study might be the antibody used in the IHC test and that we retrospectively reviewed the patient cohort.…”

“…Previous studies have indicated that TTF-1 positive lung adenocarcinomas are dependent on the sustained expression of TTF-1 and that they sometimes exhibit focal copy number increases 4,13 . Despite its role as a “lineage-survival” oncogene in lung ADC, it has become apparent that TTF-1 expression is associated with a favorable prognosis in NSCLC, and some recent research found TTF-1 can modulate the sensitivity to cisplatin and connect with mutated EGFR, TTF-1 positive patients also display more favorable factors like actionable target mutation 19–22 . As more signaling partners of NKX2-1 are revealed, there will be opportunities to initiate translational research for creating and developing NKX2-1-dependent strategies as tools for managing NKX2-1–positive lung cancer.…”