Crizotinib Resistance Can Potentially Be Reversed

A new study shows that genes can become sensitive to crizotinib after the introduction of ponatinib.

In a study published in the Journal of Thoracic Oncology, researchers found no change in the proto-oncogene 1 receptor tyrosine kinase (ROS1) fusion gene in non-small cell lung cancer tumors resistant to crizotinib compared with the pretreatment tumor samples by FISH analysis or DNA sequencing.

Crizotinib is a small-molecule tyrosine kinase inhibitor that results in tumor regression in most initial cases.

Patients treated with crizotinib commonly become resistant to the drug and the disease progresses.

In this study, researchers conducted molecular analysis on tumor samples from a proto-oncogene 1 receptor tyrosine kinase positive (ROS1+) 38-year-old woman diagnosed with stage IV lung adenocarcinoma.

Tumor biopsies were collected before and again after 15 months of crizotinib treatment.

After 15 months, crizotinib resistance was noted and the disease progressed.

Researchers used fluorescence in situ hybridization (FISH) analysis or DNA sequencing on tumor samples in an attempt to identify a gain or loss in the ROS1 fusion gene.

SNaPshot was also used to identify any new mutations.

New mutations were grown in vitro. Researchers then exposed the mutated genes to drugs that targeted these genes and measured cell proliferation.

The study showed no change in the ROS1 fusion gene in both pretreatment tumor samples as well as crizotinib resistant samples.

The new mutation in the KIT gene encoding the amino acid substitution, pD816G, was found.

According to researchers, the drug ponatinib showed inhibition of KITD816 activity. In ROS1+ cells expressing KITD816G, adding ponatinib make the cells sensitive to crizotinib again.

"Although our results demonstrate that ponatinib can overcome KIT-mediated resistance in vitro, it remains unknown whether ponatinib can overcome this or other KIT activating mutations in patients,” the study authors said in a press release. “Detection of KIT mutations may allow enrollment of patients with ROS1+ cancer (or other oncogenes), onto clinical trials of KIT inhibitors, however it is likely that dual inhibition of both KIT and ROS1 would need to be maintained based on our results."