Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF β -Induced EMT in Human Non-Small Cell Lung Cancer

• Published in: International journal of molecular sciences Vol. 24; no. 2; p. 1475
• Main Authors: Andreucci, Elena, Bugatti, Kelly, Peppicelli, Silvia, Ruzzolini, Jessica, Lulli, Matteo, Calorini, Lido, Battistini, Lucia, Zanardi, Franca, Sartori, Andrea, Bianchini, Francesca
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.01.2023; MDPI
• Subjects: A549 lung cancer cells; Adenocarcinoma; Antineoplastic Agents - pharmacology; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell adhesion & migration; Cell growth; Cell Line, Tumor; Conjugates; Epithelial-Mesenchymal Transition; epithelial-mesenchymal transition (EMT); Fibroblasts; Fibronectin; Genotype & phenotype; Growth factors; Humans; Integrins - metabolism; Kinases; Ligands; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical prognosis; Mesenchyme; molecular conjugates; nintedanib; Non-small cell lung carcinoma; Phenotypes; Proteins; Transforming Growth Factor beta - metabolism; transforming growth factorβ (TGFβ); Tumor Microenvironment; αvβ6 integrin ligands; transforming growth factorβ (TGFβ); αvβ6 integrin ligands; epithelial-mesenchymal transition (EMT); molecular conjugates; nintedanib; A549 lung cancer cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24021475

Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGF is one of the most powerful inducers of this transition, as it induces overexpression of the fibronectin receptor, αvβ6 integrin, in cancer cells which, in turn, is strongly associated with EMT. Thus, αvβ6 integrin receptors may be exploited as a target for the selective delivery of anti-tumor agents. We introduce three novel synthesized conjugates, in which a selective αvβ6 receptor ligand is linked to nintedanib, a potent kinase inhibitor used to treat advanced adenocarcinoma lung cancer in clinics. The αvβ6 integrin ligand directs nintedanib activity to the target cells of the tumor microenvironment, avoiding the onset of negative side effects in normal cells. We found that the three conjugates inhibit the adhesion of cancer cells to fibronectin in a concentration-dependent manner and that αvβ6-expressing cells internalized the conjugated compounds, thus permitting nintedanib to inhibit 2D and 3D cancer cell growth and suppress the clonogenic ability of the EMT phenotype as well as intervening in other aspects associated with the EMT transition. These results highlight αvβ6 receptors as privileged access points for dual-targeting molecular conjugates engaged in an efficient and precise strategy against non-small cell lung cancer.