A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer

Abstract

Purpose Rearranged ROS1 is a crizotinib-sensitive oncogenic driver in lung cancer. The development of acquired resistance, however, poses a serious clinical challenge. Consequently, experimental and clinical validation of resistance mechanisms and potential second-line therapies is essential. Experimental Design We report the discovery of a novel, solvent-front ROS1D2033N mutation in a patient with CD74-ROS1-rearranged lung adenocarcinoma and acquired resistance to crizotinib. Crizotinib-resistance of CD74-ROS1D2033N was functionally evaluated using cell based assays and structural modelling. Results In biochemical and cell-based assays, the CD74-ROS1D2033N mutant demonstrated significantly decreased sensitivity to crizotinib. Molecular dynamics simulation revealed compromised crizotinib binding due to drastic changes in the electrostatic interaction between the D2033 residue and crizotinib and reorientation of neighboring residues. In contrast, cabozantinib binding was unaffected by the D2033N substitution and inhibitory potency against the mutant was retained. Notably, cabozantinib treatment resulted in a rapid clinical and near complete radiographic response in this patient. Conclusions These results provide the first example of successful therapeutic intervention with targeted therapy to overcome crizotinib resistance in a ROS1-rearranged cancer.

Molecular Pathology of Lung Cancer

“…Gelişen direncin altında yatan tüm mekanizmalar henüz ortaya konamamış olsa da, kazanılmış ikincil ROS1 mutasyonlarının bir kısım krizotinib direncinden sorumlu olduğu gösterilmiştir (26). Bu hastaların "cabozantinib" gibi birden çok hedefi bulunan tirozin kinaz inhibitörlerine cevap verebildiği saptanmıştır (27).…”

Lorlatinib in ALK- and ROS1-positive NSCLC: the future has a start

“…Therefore, potential options of treatment sequence involve crizotinib (or ceritinib) followed by lorlatinib, taking into account its inefficiency on G2032R ROS1 mutation. Additional "large spectrum" inhibitors such as cabozantinib have shown their role in crizotinib-resistant ROS1-positive NSCLC, with a relevant toxicity and without strict documentation of clinical effectiveness against G2032R mutant (13,16).…”

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance

“…There is limited data available on the mechanisms of acquired resistance to crizotinib in ROS1 positive NSCLC, however several secondary ROS1 mutations that can cause resistance have been identified, for example the G2026M mutation (gatekeeper) or the L2155S solvent-front (D2033N) mutation which can still respond to the multi-targeted TKI, cabozantinib which has ROS inhibitory activity as well (78)(79)(80).…”