SELLAS Life Sciences Group announced positive preclinical data indicating that ASXL1 mutations may predict response to SLS009 in solid cancers. The data suggests that SLS009, a selective CDK9 inhibitor, exhibits high efficacy in ASXL1-mutated solid cancer cell lines, potentially offering a targeted therapeutic approach.
The research explored the frequency of ASXL1 mutations in colorectal cancer (CRC) with high microsatellite instability (MSI-H) and non-small cell lung cancer (NSCLC), and whether these mutations could predict SLS009 efficacy, similar to observations in acute myeloid leukemia (AML).
Preclinical Findings
Experiments involved exposing patient-derived cell lines (PDCs) to varying concentrations of SLS009 and determining the inhibitory concentration (IC50) for each line. High efficacy was defined as IC50 < 100 nM, based on observed SLS009 concentrations in patients (~400 nM). The results showed:
- In CRC MSI-H, 58% of PDCs had ASXL1 mutations, aligning with predicted frequencies.
- In NSCLC, 33% of cell lines exhibited ASXL1 mutations, higher than the predicted 2.6%.
- Overall, 67% of ASXL1-mutated solid cancer cell lines showed high SLS009 efficacy, compared to 0% in non-mutated lines.
- Specifically, in CRC MSI-H, 57% of ASXL1-mutated cell lines demonstrated high efficacy, while in NSCLC, 100% of ASXL1-mutated cell lines responded.
Implications for Targeted Therapy
"These findings are incredibly encouraging and validate our approach to developing a targeted solid tumor therapy," said Dr. Dragan Cicic, Senior Vice President, Chief Development Officer at SELLAS. He added that the study is, to the best of their knowledge, the first to identify ASXL1 mutations as a potential biomarker for drug response in solid cancers. The company has filed for provisional patent protection for the use of ASXL1 mutations as a predictive diagnostic.
About SLS009
SLS009 is a potentially first-in-class, differentiated small molecule CDK9 inhibitor with reduced toxicity and increased potency compared to other CDK9 inhibitors. Clinical data suggests that SLS009 demonstrated a high response rate in AML patients with unfavorable prognostic factors including ASXL1 mutation.
