Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins.
The rapidly growing recognition of the role of oncogenic ROS1 fusion proteins in the malignant transformation of multiple cancers, including lung adenocarcinoma, cholangiocarcinoma, and glioblastoma, is driving efforts to develop effective ROS1 inhibitors for use as molecularly targeted therapy. Using a multidisciplinary approach involving small molecule screening in combination with in vitro and in vivo tumor models, we show that foretinib (GSK1363089) is a more potent ROS1 inhibitor than crizotinib (PF-02341066), an ALK/ROS inhibitor currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Whereas crizotinib has demonstrated promising early results in patients with ROS1-rearranged non-small-cell lung carcinoma, recently emerging clinical evidence suggests that patients may develop crizotinib resistance due to acquired point mutations in the kinase domain of ROS1, thus necessitating identification of additional potent ROS1 inhibitors for therapeutic intervention. We confirm that the ROS1(G2032R) mutant, recently reported in clinical resistance to crizotinib, retains foretinib sensitivity at concentrations below safe, clinically achievable levels. Furthermore, we use an accelerated mutagenesis screen to preemptively identify mutations in the ROS1 kinase domain that confer resistance to crizotinib and demonstrate that these mutants also remain foretinib sensitive. Taken together, our data strongly suggest that foretinib is a highly effective ROS1 inhibitor, and further clinical investigation to evaluate its potential therapeutic benefit for patients with ROS1-driven malignancies is warranted.
Knight Cancer Institute, Howard Hughes Medical Institute, and Departments of Biochemistry and Molecular Biology and Cell and Developmental Biology, Oregon Health and Sciences University, Portland, OR 97239.
Monika A
MA
Davare
Anna
A
Saborowski
Christopher A
CA
Eide
Cristina
C
Tognon
Rebecca L
RL
Smith
Johannes
J
Elferich
Anupriya
A
Agarwal
Jeffrey W
JW
Tyner
Ujwal P
UP
Shinde
Scott W
SW
Lowe
Brian J
BJ
Druker
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009857:Oncogenes / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D017422:Sequence Analysis, DNA
D000813:Anilides; D017931:DNA Primers; C544831:GSK 1363089; D011518:Proto-Oncogene Proteins; D011804:Quinolines; D020794:Receptor Protein-Tyrosine Kinases; C483813:Ros1 protein, mouse