crizotinib and Mouth-Neoplasms

We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM).. We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis. Sensitivity to pharmacological Met inhibition was tested invitro in premalignant and OC cell lines (n = 33) and invivo using the 4-NQO model of oral chemoprevention (n = 20 mice per group). All statistical tests were two-sided.. The overlap of 693 transcripts associated with an increased risk of OC with 163 transcripts overexpressed in OC compared with NM led to the identification of 23 overlapping transcripts, including MET. MET overexpression in OL was associated with a hazard ratio of 3.84 (95% confidence interval = 1.59 to 9.27, P = .003) of developing OC. Met activation was found in OC and preneoplastic cell lines. Crizotinib activity in preneoplastic and OC cell lines was comparable. ARQ 197 was more active in preneoplastic compared with OC cell lines. In the 4-NQO model, squamous cell carcinoma, dysplasia, and hyperkeratosis were observed in 75.0%, 15.0%, and 10.0% in the control group, and in 25.0%, 70.0%, and 5.0% in the crizotinib group (P < .001).. Together, these data suggest that MET activation may represent an early driver in oral premalignancy and a target for chemoprevention of OC.

Topics: 4-Nitroquinoline-1-oxide; Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Case-Control Studies; Cell Proliferation; Crizotinib; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Genomics; Head and Neck Neoplasms; Humans; Leukoplakia, Oral; Male; Mice, Inbred CBA; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Neoplasm Invasiveness; Precancerous Conditions; Prognosis; Prospective Studies; Proto-Oncogene Proteins c-met; Pyrrolidinones; Quinolines; Quinolones; Survival Rate; Tumor Cells, Cultured

c-Src inhibition in cancer cells leads to an abrogation of invasion but a variable effect on apoptosis. The pathways downstream of c-Src promoting survival are not well characterized. Because cancer therapy that both decreases invasion and induces significant apoptosis would be ideal, we sought to characterize the mechanisms of resistance to c-Src inhibition.. c-Src was inhibited in a panel of oral cancer cell lines and subsequent survival and signaling measured. The interactions between c-Src and c-Met were evaluated using immunoprecitation and an in vitro kinase assay. Cytotoxicity was measured and the Chou-Talalay combination index calculated. An orthotopic model of oral cancer was used to assess the effects of c-Met and c-Src inhibitors.. Inhibition of c-Src resulted in c-Met inhibition in sensitive cells lines, but not in resistant cell lines. Isolated c-Met was a c-Src substrate in both sensitive and resistant cells, but there was no interaction of c-Src and c-Met in intact resistant cells. To examine the biological consequences of this mechanism, we demonstrated synergistic cytotoxicity, enhanced apoptosis, and decreased tumor size with the combination of c-Src and c-Met inhibitors.. Sustained c-Met activation can mediate resistance to c-Src inhibition. These data suggest that the differences between c-Met and c-Src signaling in sensitive and resistant cells are due to distinct factors promoting or inhibiting interactions, respectively, rather than to intrinsic structural changes in c-Src or c-Met. The synergistic cytotoxic effects of c-Src and c-Met inhibition may be important for the treatment of head and neck cancers.

Topics: Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Survival; Crizotinib; CSK Tyrosine-Protein Kinase; Dasatinib; Drug Interactions; Drug Resistance, Neoplasm; Humans; Mice; Mice, Nude; Mouth Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; src-Family Kinases; Thiazoles