In 2011, the drug crizotinib was approved for use with the subset of non-small cell lung cancer (NSCLC) patients with chromosomal rearrangements involving the ALK gene, or simply “ALK-positive” patients. Unfortunately (as with many drugs) ALK+ NSCLC tends to develop resistance to crizotinib.
A University of Colorado Cancer Center study presented today at the American Society of Clinical Oncology annual meeting in Chicago, Ill. uses human tumor samples to show the mechanisms of this resistance.
When ALK is targeted, human tumors can switch their dependence from ALK to either KRAS or EGFR mutations.
“At the time of crizotinib resistance, doctors might recommend a clinical trial with a second-gen ALK inhibitor – that is, unless we discover via biopsy that the tumor has shifted its dependence to, for example, KRAS or EGFR. In that case, a second-gen ALK inhibitor is unlikely to do as much good as a drug that targets one of these other mutations,” says Robert Doebele, MD, PhD, investigator at the CU Cancer Center and assistant professor of medical oncology at the CU School of Medicine.
“It’s likely these findings point toward the heterogeneity of tumors that hold within them pockets of ALK+ and perhaps also pockets harboring EGFR or KRAS mutations. When we target ALK, we allow EGFR or KRAS to outcompete the ALK-dependent cells, leading to a replacement of the ALK+ cells by cells primarily driven by cells dependent on one of these other mutations,” Doebele says.
Biopsying ALK+ NSCLC tumors at time of crizotinib resistance could help match patients with successful next-line treatments or clinical trials.