Multiple Endocrine Disruption by the MET/ALK Inhibitor Crizotinib in Patients With Non-small Cell Lung Cancer.
OBJECTIVE
Non-small cell lung cancer (NSCLC) is a heterogenous group of disorders that can be subclassified based upon molecular characterization. Anaplastic lymphoma kinase translocation and MET aberrations occur in a subset of NSCLC. Anaplastic lymphoma kinase/MET have been shown to be inhibited by the small molecule tyrosine kinase inhibitor crizotinib. Recently, crizotinib was shown to decrease testosterone in males. Herein, we describe the effects of crizotinib on multiple hormonal axes.


METHODS
Seven consecutive patients with NSCLC who were receiving crizotinib as part of their standard care were evaluated for hormonal disruptions.


RESULTS
Primary hypogonadism was detected in 4/5 of males, whereas mildly elevated prolactin was observed in 4/7 patients. Hypocalcemia was observed in 3/7 patients. Interestingly, 5/7 patients had elevated levels of insulin-like growth factor-1 (IGF-1) levels, and the remaining 2 individuals had levels that were near the upper limits of the normal range.


CONCLUSIONS
Because of cellular cross-talk between MET and IGF-1 signaling, elevated IGF-1 levels induced by crizotinib treatment may have implications for long-term drug efficacy. Furthermore, this finding suggests a potential avenue of therapeutic synergy, namely coordinate inhibition of the MET and IGF-1 signaling pathways. Finally, as crizotinib has been recently approved, it is prudent to check hormone and calcium biomarkers and correct noted deficiencies for improved outcomes and quality of life.
*Section of Endocrinology, Diabetes, and Metabolism †Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL.
Robert M
RM
Sargis
Ravi
R
Salgia
D000077548:Anaplastic Lymphoma Kinase; D002118:Calcium / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000077547:Crizotinib; D052244:Endocrine Disruptors / Q000009:adverse effects; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000139:chemically induced; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008175:Lung Neoplasms / Q000188:drug therapy*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012016:Reference Values; D013739:Testosterone / Q000097:blood
D052244:Endocrine Disruptors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D013739:Testosterone; D000077547:Crizotinib; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D002118:Calcium