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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
MINI27.14 - The Aurora Kinase B Inhibitor AZD1152-HQPA Inhibitor in Small Cell Lung Cancer (SCLC) (ID 2161)
16:45 - 18:15 | Author(s): D. Chan
Aurora kinase expression has been associated with a poor prognosis in non-small cell lung cancer (NSCLC) and aurora kinase inhibitors have activity in preclinical lung models. Aurora kinases are required for mitosis and cell division. Small cell lung cancer cells have rapid proliferation and higher rates of MYC family amplification, which makes aurora kinase inhibition a natural target.
23-SCLC lines with known MYC family amplification and MYC family gene expression were exposed to varying concentrations of the specific aurora kinase B inhibitor AZD1152-HQPA. The percentage growth inhibition compared to control was determined in MTS assays at 120 hours. Cell lines were classified as “sensitive” if the GI50 concentration was < 50 nM and with ≥ 80% growth inhibition at 100 nM. Fisher’s exact test was used to determine the correlation between amplification of MYC family members and sensitivity of the cell lines to growth inhibition by AZD1152-HQPA. A two-group t-test (gene expression as a continuous variable) and an odds ratio estimate (dichotomized gene expression level) were used to determine a correlation between MYC family gene expression and growth inhibition by AZD1152-HQPA. To determine whether growth inhibition correlated with the published MYC-signature gene expression, we used Fisher’s exact test. In vivo growth inhibition by AZD1152 (prodrug) was evaluated on SCLC xenografts in nude mice.
Nine (39%) of the 23 cell lines were sensitive to AZD1152-HQPA with IC50 values < 50 nM. There was a significant association between sensitivity to growth inhibition by AZD1152-HQPA and cMYC amplification (p = 0.018). The odds of being sensitive is 16 (95% CI, 1.4, 183) times higher for cMYC amplified compared to non-cMYC amplified cell lines. By a two-group t-test, the mean cMYC gene expression of 10.9 (std 4) in sensitive lines compared to 7.2 (std 3.3) in resistant lines was also significant (p = 0.026). Cell lines were separated into two groups based on cMYC gene expression > 12.9 vs < 12.9. The odds of being sensitive is 11 (95% CI, 1.2, 103) time higher for cell lines with cMYC gene expression > 12.9 compared to cell lines with cMYC gene expression < 12.9. Sensitive cell lines were enriched in a published MYC-signature of gene expression (p = 0.042). AZD1152 (prodrug) caused significant growth delay in vivo in two of these lines. The doses of AZD1152-HQPA used in this study are within the range reported to be clinically achievable.
Aurora kinase inhibitors have promise in SCLC therapy. Questions that currently need answering in translating aurora kinase inhibitors in the clinical setting are: (1) the dosing schedule to avoid myelosupression, (2) should aurora kinase inhibitors be used in maintenance therapy and (3) should the aurora kinase inhibitors be evaluating in combination with chemotherapy.
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