Inhibition of ACK1 delays and overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib. (December 2020)

• Record Type: Journal Article
• Authors: Gu, Jiajia; Qian, Luxi; Zhang, Guojing; Mahajan, Nupam P.; Owonikoko, Taofeek K.; Ramalingam, Suresh S.; Sun, Shi-Yong
• Is Part Of: Lung cancer. Volume 150(2020)
• Page Start: 26
• Page End: 35
• Publication Date: 2020-12
• Subjects: ACK1 -- Osimertinib -- Acquired resistance -- EGFR -- Apoptosis -- Lung cancer; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2020.09.023
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: ACK1 inhibition synergizes with osimertinib against EGFR mutant NSCLC cells. ACK1 inhibition delays emergence of osimertinib resistance in vitro and in vivo . Targeting ACK1 restores the response of osimertinib-resistant cells to osimertinib. Targeting ACK1 as a novel strategy to delay and overcome osimertinib resistance. Abstract: Objectives: The emergence of acquired resistance to the third generation EGFR inhibitor, osimertinib (AZD9291 or TAGRISSO™), is an unavoidable huge clinical challenge. The involvement of ACK1, a non-receptor tyrosine kinase with an oncogenic function, in regulating cell response to osimertinib has not been investigated and thus is the focus of this study. Material and Methods: Drug effects on cell growth were evaluated by measuring cell numbers and colony formation. Apoptosis was monitored with flow cytometry for annexin V-positive cells and Western blotting for protein cleavage. Intracellular protein and mRNA alterations were detected with Western blotting and qRT-PCR, respectively. Drug effects on delaying osimertinib acquired resistance were determined using colony formation in vitro and xenografts in nude mice in vivo, respectively. Cell senescence was assayed by β-galactosidase staining. Results: Inhibition of ACK1 with the novel ACK1 inhibitor, ( R )-9b synergized with osimertinib in inhibiting the growth of EGFR mutant NSCLC cell lines. Similar results were also generated with ACK1 gene knockdown. The combination of osimertinib and ( R )-9b enhanced induction of apoptosis. In both in vitro and in vivo long-term resistance delay assays, the combination of ( R )-9b and osimertinib clearly delayed the emergence of osimertinib-resistance. Further, the ( R )-9b and osimertinib combination was also effective in inhibiting the growth of EGFR mutant NSCLC cell lines with acquired resistance to osimertinib, which possess elevated levels of ACK1, and the growth of osimertinib-resistant tumors in vivo . In some resistant cell lines, the combinations induced senescence in addition to induction of apoptosis. Conclusions: These novel findings suggest that ACK1 inhibition might be a potential and innovative strategy for delaying and overcoming osimertinb acquired resistance.