Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection.
Dasatinib is a multitargeted kinase inhibitor that was recently approved for the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. It is also in clinical trials for treating patients with solid tumors. The identification of molecular markers predictive of response to dasatinib could assist in clinical development by selecting patients most likely to derive clinical benefit. Using baseline gene expression profiling of a panel of 23 breast cancer cell lines, we identified genomic signatures highly correlated with in vitro sensitivity to dasatinib. The ability of these signatures to predict dasatinib sensitivity was further confirmed and validated in independent test cell lines. A six-gene model was used to correctly predict dasatinib sensitivity in 11 out of 12 (92%) additional breast and 19 out of 23 (83%) lung cancer cell lines. Quantitative real-time PCR and immunohistochemical assays further confirmed the differential expression pattern of selected markers. Finally, these gene signatures were observed in a subset of primary breast, lung, and ovarian tumors suggesting potential utility in patient selection. The subset of breast cancer patients expressing the dasatinib-sensitive signature includes a distinct clinical and molecular subgroup: the so-called "triple negative" (i.e., estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) or "basal" breast cancer subtype. This patient population has a poor prognosis and currently has few effective treatment options. Our results implicate that dasatinib may represent a valuable treatment option in this difficult-to-treat population. To test this hypothesis, clinical studies are now under way to determine the activity of dasatinib in these patients.
Huang
Fei
F
Departments of Clinical Discovery and Oncology Discovery, Bristol-Myers Squibb Co., Princeton, NJ 08543, USA. fei.huang@bms.com
Reeves
Karen
K
Han
Xia
X
Fairchild
Craig
C
Platero
Suso
S
Wong
Tai W
TW
Lee
Francis
F
Shaw
Peter
P
Clark
Edwin
E
D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D008957:Models, Genetic; D018579:Patient Selection; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib