Alk inhibitors in non-small cell lung cancer: drug resistance mechanisms and a new therapeutic strategy

Mahgol Moaref dezfouli,1,* Mohammad amin dehghani,2 Fatemeh dehghani,3

1. School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2. Student Research Committee of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3. Department of Genetics, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract


Introduction

In patients with non-small-cell lung cancer (nsclc), rearrangement of the anaplastic lymphoma kinase (alk) occurs. there is an invariable improvement in alk despite its sensitivity to tyrosine kinase inhibitors (alk inhibitors). this is mostly associated with brain growth. treatments for nsclc, which is occurred due to the rearrangement of alk, include crizotinib and alectinib. nonetheless, there is no clear statistics on the effectiveness of these inhibitors on the patients’ overall survival, who are diagnosed with alk-rearranged nsclc.

Methods

To perform this study, we searched the english articles that were recently published in pubmed database and based on the results shown in the latest meetings applying the keywords of drug resistance, alk inhibitors, non-small cell lung cancer, target therapy, and alk.

Results

In this research, it was found that the second-generation alk inhibitors have been recently assessed in first-line treatment. according to the results, while there were resistance mutations in alk, ceritinib was extremely active in patients diagnosed with alk-rearranged nsclc (advanced state), even those individuals whose disease was advanced during treatment by crizotinib. on the other hand, proper clinical activity and toleration by patients with alk-positive nsclc experiencing disease progression during crizotinib treatment were reported for alectinib. moreover, numerous crizotinibresistant mutations can be controlled by the second-generation alk inhibitor ceritinib, which is also effective against various laboratory models of acquired resistance to crizotinib in vivo and in vitro.

Conclusion

According to the results of the study, patients with alk-positive disease experiencing disease progression during crizotinib treatment could be properly treated by alectinib and ceritinib. with these results, a molecular basis is created for the mentioned clinical activities of alectinib and ceritinib in patients with alk-positive nsclc who are resistance to crizotinib.

Keywords

Non-small cell lung cancer; alk; alk inhibitors; drug resistance; target therapy