New insights into the efficacy of nintedanib therapy

By Naveed Saleh, MD, MS, for MDLinx
Published December 13, 2019

Key Takeaways

About 85% of lung cancer cases are non-small cell lung cancer (NSCLC), of which about 50% are adenocarcinomas (ADCs), 40% are squamous cell carcinomas (SCCs), and the rest are less common subtypes. Researchers uncovered molecular mechanisms identifying which patients with NSCLC may benefit from nintedanib, an antiangiogenic and antifibrotic drug, according to a study published in Cancer Research.

“Since fibrosis is a common adverse effect induced by radiotherapy toxicity, our results suggest patients with adenocarcinoma (especially non-smokers) who receive radiotherapy could benefit from antifibrotic drugs such as nintedanib combined with radiotherapy,” stated lead author Jordi Alcaraz, PhD, Department of Biomedicine, University of Barcelona, Spain. “Likewise, since fibrosis is associated with immunosuppression and tumor growth, our results support that patients with adenocarcinoma could benefit from the combination of antifibrotic drugs like nintedanib with immunotherapy.”

“The results describe for the first time that tumor fibrosis is higher in [ADC] than in [SCC], which causes patients with [ADC] to respond better to treatment with nintedanib. Furthermore, we identify the underlying mechanism: the pro-fibrotic transcription factor SMAD3 in fibroblasts—the main cells that drive fibrosis—is more epigenetically repressed in [SCC] than in [ADC], and this makes patients with [SCC] to have less fibrosis and to be resistant to nintedanib,” he added.

Tumor-associated fibroblasts (TAFs) widely populate tumor-promoting fibrotic stroma, with this TAF-rich stroma piquing interest as a potential drug target. In a previous trial conducted by Dr. Alcaraz and colleagues involving NSCLC, nintedanib ameliorated outcomes in those with ADC but not those with SCC.

As demonstrated by inordinate positivity in histologic stainings for fibrillar collagens, alpha-smooth muscle actin (α-SMA), and other fibroblast activation markers in NSCLC biopsy samples, lung TAFs harbor an activated/pro-fibrotic phenotype, which results in a more fibrotic stroma. Furthermore, these fibrosis markers predict decreased survival.

Similarly, the potent fibroblast activator cytokine transforming growth factor-β1 (TGF-β1), which is upregulated in NSCLC, predicts decreased survival.

Dr. Alcaraz and colleagues had recently reported that, compared with patient-matched control fibroblasts, SMAD3, which is an integral pro-fibrotic transcription factor of the TGF-β pathway, was epigenetically down-regulated via promoter hypermethylation in lung TAFs—a paradoxical finding.

“Altogether, these previous results support the hypothesis that TGF-β1/SMAD3 signaling goes awry in lung TAFs, and that such alteration may depend on the histologic subtype, which could be associated with the distinct nintedanib effects in ADC and SCC,” wrote the researchers.

From a mechanistic perspective, compared with that of ADC-TAFs, the decreased fibrosis and nintedanib response of SCC-TAFs may be related to higher promoter methylation of the pro-fibrotic TGF-β transcription factor SMAD3, which lead to compensatory TGF-β1/SMAD2 activation.

“Consistently, forcing global DNA demethylation of SCC-TAFs with 5-AZA rescued TGF-β1/SMAD3 activation, whereas genetic downregulation of SMAD3 in ADC-TAFs and control fibroblasts increased TGF-β1/SMAD2 activation, and reduced their fibrotic phenotype and antitumor responses to nintedanib in vitro and in vivo,” the authors wrote.

Moreover, the researchers discovered that cigarette smoke, as well as the location of SCC at the level of the proximal airways where smoke pours in, may prime SCC-TAFs to stronger SMAD3 epigenetic repression because cigarette smoke preferentially increases SMAD3.

The researchers concluded that their results demonstrate that histotype-specific regulation of tumor fibrosis in lung cancer is facilitated via differential SMAD3 promoter methylation in TAFs.

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