Novel FAK inhibitors suppress tumor growth and reverse EGFR-TKI resistance in non-small cell lung cancer

  • Cancer Drug Resist. 2025 Nov 5:8:57. doi: 10.20517/cdr.2025.139.
Geng Xu  1  2 ,  Camilla Pecoraro  1  3 ,  Mahrou Vahabi  1 ,  Dongmei Deng  2 ,  Andrea Cavazzoni  4 ,  Hamid Fiuji  5 ,  Costanza Anna Maria Lagrasta  4 ,  Stella M Cascioferro  3 ,  Marcello Tiseo  4  6 ,  Daniela Carbone  3 ,  Amir Avan  5  7 ,  Paolo A Zucali  8  9 ,  Yehuda G Assaraf  10 ,  Godefridus J Peters  1  11 ,  Patrizia Diana  3 ,  Elisa Giovannetti  1  12
Affiliations
  • 1. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit University, Amsterdam 1081 HV, the Netherlands.
  • 2. Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam 1081 LA, the Netherlands.
  • 3. Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo 90128, Italy.
  • 4. Department of Medicine and Surgery, University of Parma, Parma 43126, Italy.
  • 5. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 9177899191, Iran.
  • 6. Department of Oncology and Hematology, Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy.
  • 7. Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane 4059, Australia.
  • 8. Department of Oncology, IRCCS Humanitas Research Hospital, Rozzano 20089, Italy.
  • 9. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20072, Italy.
  • 10. The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
  • 11. Department of Biochemistry, Medical University of Gdansk, Gdansk 80-211, Poland.
  • 12. Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, San Giuliano 56017, Italy.
PMID: 41281943 DOI: 10.20517/cdr.2025.139
Abstract

Aim: The current study aims to investigate the critical role of the focal adhesion kinase (FAK) oncogenic signaling pathway in mediating drug resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) and evaluate the potential of two novel FAK inhibitors, 10k and 10l, as therapeutic strategies for drug resistant non-small cell lung Cancer (NSCLC). Methods: EGFR-TKI resistance in NSCLC cells was developed via stepwise drug selection. Kinases/polymerase chain reaction (PCR) arrays identified key resistance determinants, while reverse transcription quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry evaluated FAK messenger RNA and phosphorylation levels. Antitumor activities were assessed using sulforhodamine-B, clonogenic, wound-healing, and Apoptosis assays, spheroids and xenografts. Results: FAK was identified as a key driver of acquired resistance to EGFR-TKIs. High FAK expression predicted poor prognosis in patients treated with EGFR-TKIs. Kinase and PCR profiling confirmed elevated FAK levels as a resistance mechanism. Compounds 10k and 10l reduced phosphorylated FAK and showed strong anti-proliferative, anti-migratory, and pro-apoptotic effects in both EGFR-TKI-sensitive and -resistant cells. Notably, these compounds were shown to resensitize resistant NSCLC cells to EGFR-TKIs, with 10k inhibiting tumor growth and enhancing Osimertinib efficacy in resistant xenografts. Conclusion: These findings not only uncover a pivotal mechanism of EGFR-TKI drug resistance but also highlight innovative, promising therapeutic options for patients with therapy-refractory disease.

Keywords
Afatinib; EGFR-TKI resistance; Focal adhesion kinase (FAK); Osimertinib; non-small cell lung cancer (NSCLC).
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