Loss of cellular identity in common pre-clinical models of serine‑threonine kinase 11 (Liver kinase B1) loss

Karthikeyan, Santhosh Kumar; Gimbrone, Nicholas T.; Percy, Trent R; Cress, W. Douglas

doi:10.1016/j.ctarc.2020.100286

Cited by 4 publications

(3 citation statements)

References 41 publications

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“… 35 , 36 In preclinical models, TTF‐1 negativity is associated with loss of serine–threonine kinase 11 (STK11), which also negatively correlates with ICI effectiveness. 37 , 38 , 39 , 40 Furthermore, uncommon histological type of adenocarcinoma such as invasive mucinous adenocarcinomas and enteric adenocarcinomas frequently exhibited TTF‐1 negative status and those cancers are known to be less responsive to ICI. 41 , 42 , 43 Although the present study did not assess the KEAP1 and/or STK11 gene alterations and the detailed types of adenocarcinomas, above‐mentioned reports might partially explain why TTF‐1 negative lung adenocarcinoma showed worse outcomes with ICI monotherapy in our study.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that TTF‐1 negative lung adenocarcinoma had more frequent Kelch‐like epichlorohydrin‐associated protein 1 (KEAP1) mutations, which negatively affect ICI efficacy, than TTF‐1 positive lung adenocarcinoma 35,36 . In preclinical models, TTF‐1 negativity is associated with loss of serine–threonine kinase 11 (STK11), which also negatively correlates with ICI effectiveness 37–40 . Furthermore, uncommon histological type of adenocarcinoma such as invasive mucinous adenocarcinomas and enteric adenocarcinomas frequently exhibited TTF‐1 negative status and those cancers are known to be less responsive to ICI 41–43 .…”

Section: Discussionmentioning

confidence: 99%

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Association of thyroid transcription factor‐1 with the efficacy of immune‐checkpoint inhibitors in patients with advanced lung adenocarcinoma

Nakahama

Osawa²,

Izumi

et al. 2022

Thoracic Cancer

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Background We aimed to identify the relationship between thyroid transcription factor‐1 (TTF‐1) expression of lung adenocarcinoma and the efficacy of immune‐checkpoint inhibitor (ICI) therapy. Methods This retrospective multicenter study comprised patients with advanced lung adenocarcinoma treated with ICI monotherapy. We collected clinical medical records including data on TTF‐1 expression and analyzed the relationship between TTF‐1 expression and programmed death‐ligand 1 tumor proportion score (PD‐L1 TPS), objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Results In total, 108 patients with lung adenocarcinoma were analyzed. The rate of TPS ≥1% and ≥50% in patients with positive TTF‐1 expression was significantly higher than that in patients with negative TTF‐1 expression (88% vs. 60%, p < 0.001; 65% vs. 24%, p < 0.001). The ORR was significantly higher in TTF‐1 positive patients than in TTF‐1‐negative patients (38% vs. 8%, p = 0.003). Among patients with TPS ≥50% and 1%–49%, the ORR in TTF‐1 positive and negative patients was 48% (26/54) versus 17% (1/6) ( p = 0.21), and 32% (6/19) versus 11% (1/9) ( p = 0.37), respectively. The ORR for patients with TPS <1% was 0% in both the TTF‐1 negative and positive cases. The median PFS and OS was significantly longer in TTF‐1‐positive patients than in TTF‐1‐negative patients (5.4 vs. 1.6 months, p < 0.001; 18.2 vs. 8.0 months, p = 0.041). Multivariate analysis revealed that TTF‐1‐negative status was an independent unfavorable prognostic factor for PFS. Conclusion Patients with TTF‐1‐positive status receiving ICI monotherapy showed better outcomes than those with TTF‐1‐negative lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of thyroid transcription factor‐1 with the efficacy of immune‐checkpoint inhibitors in patients with advanced lung adenocarcinoma

Nakahama

Osawa²,

Izumi

et al. 2022

Thoracic Cancer

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show abstract

“…We also note the fraction of patients with poor PS was higher in TTF-1-negative compared to TTF-1-positive individuals. TTF-1-negative status is related to a higher frequency of serine-threonine kinase 11 ( STK11 ) and Kelch-like epichlorohydrin-associated protein 1 ( KEAP1 ) mutations ( 18 , 19 ). These mutations are associated with a tumor microenvironment that has a lower density of tumor-infiltrating leukocytes and cytotoxic CD8 + T lymphocytes, and lower PD-L1 expression ( 20 - 24 ).…”

Section: Discussionmentioning

confidence: 99%

Thyroid transcription factor-1 (TTF-1) expression and the efficacy of combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapy in non-squamous non-small cell lung cancer

Iso,

Hisakane,

Mikami

et al. 2023

Transl Lung Cancer Res

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Background Thyroid transcription factor-1 (TTF-1) is expressed in approximately 70% of lung adenocarcinomas and is one of the most reliable makers to distinguish primary lung adenocarcinoma from metastatic disease. TTF-1-negative status is a poor prognostic factor, and TTF-1-negative lung adenocarcinoma is associated with poor efficacy of immune checkpoint inhibitor (ICI) monotherapy. However, the relationship between TTF-1 expression and the efficacy of ICI plus chemotherapy is still unclear. Methods We performed a retrospective analysis of 129 consecutive patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC) treated with ICI monotherapy or ICI plus chemotherapy between January 2016 and December 2021. The expression of programmed death ligand-1 (PD-L1) and TTF-1 was also determined in cases for which no previous data were available. We then evaluated the association between TTF-1 expression status and treatment efficacy. Results Of the 129 cases, 33 were TTF-1-negative and 96 were positive. In the ICI monotherapy group (N=70), progression-free survival (PFS) was not significantly different between TTF-1-positive and negative patients (median 3.6 vs. 3.8 months, P=0.27); however, in patients with wild-type epidermal growth factor receptor ( EGFR ) and anaplastic lymphoma kinase ( ALK ), a trend for worse PFS was observed in TTF-1-negative cases compared with those that were TTF-1-positive (median 3.8 vs. 4.5 months, P=0.088). Moreover, long-term efficacy of ICI monotherapy (>2 years) was not observed in the TTF-1-negative group. TTF-1-negative patients tended to have worse overall survival (OS) than TTF-1-positive patients (median 15.6 vs. 19.5 months, P=0.13). In the ICI plus chemotherapy group (N=59), TTF-1-negative patients tended to have better PFS and similar OS compared with TTF-1-positive patients (median 9.9 vs. 9.6 months, P=0.14; median 32.3 vs. 18.9 months, P=0.78). Long-term efficacy was generally observed in TTF-1-negative patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) (median PFS 22.5 months, median OS not reached). Conclusions ICI monotherapy is generally less efficacious in TTF-1-negative NS-NSCLC patients, and clinicians should consider ICI plus chemotherapy in these cases. Our study suggests that ABCP is an optimal regimen for TTF-1-negative NS-NSCLC.

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Effect of TTF-1 expression on progression free survival of immunotherapy and chemo-/immunotherapy in patients with non-small cell lung cancer

Uhlenbruch,

Krüger

2024

J Cancer Res Clin Oncol

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Loss of cellular identity in common pre-clinical models of serine‑threonine kinase 11 (Liver kinase B1) loss

Cited by 4 publications

References 41 publications

Association of thyroid transcription factor‐1 with the efficacy of immune‐checkpoint inhibitors in patients with advanced lung adenocarcinoma

Association of thyroid transcription factor‐1 with the efficacy of immune‐checkpoint inhibitors in patients with advanced lung adenocarcinoma

Thyroid transcription factor-1 (TTF-1) expression and the efficacy of combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapy in non-squamous non-small cell lung cancer

Effect of TTF-1 expression on progression free survival of immunotherapy and chemo-/immunotherapy in patients with non-small cell lung cancer

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