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Abstract 4032: Identification of Muc5B mutation as a positive predictive biomarker for mTORC1/2 inhibition by ATG-008 in lung cancer


 Background: mTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation, and survival. mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2) are critical mediators of the PI3K-AKT pathway. Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in solid tumors and hematological malignancies. Inhibition of mTOR by small molecule inhibitors has therefore attracted great attention as an anti-cancer therapy. However, due to relatively modest clinical efficacy, no mTOR inhibitor has been approved for the treatment of lung cancer. The research of potentially predictive biomarkers is a key aspect of all anti-tumor treatment strategies to improve the proportion of patients benefiting from therapy. Multiple genetic alternations have been reported to be correlated with better anti-tumor efficacy of mTOR inhibition in animal models or patients, such as NFE2L2 mutation, STK11 mutation, or RICTOR amplification. Here, we report Muc5B mutation as a positive predictive biomarker for mTORC1/2 inhibition by ATG-008 (Onatasertib), a dual mTORC1/2 kinase inhibitor, in preclinical lung cancer models.
 Methods: 31 different lung cancer cell lines were treated with ATG-008 in vitro to determine the dose-response curves and the Area Under Curve (AUC) values. According to the AUC, the cell lines were classified as a sensitive group, medium group, and insensitive group. Unbiased genomic analysis of the tested cell lines was used to correlate the gene mutation, amplification, and expression with the sensitivity to ATG-008. The potential positive predictive biomarker, MUC5B mutation, was further validated in lung cancer CDX mouse models. Mouse bearing lung cancer cell lines with or without MUC5B mutation were orally treated with ATG-008 to determine the in vivo tumor growth inhibition.
 Results: ATG-008 inhibits lung cancer cell growth in vitro, with IC50 values ranging from 0.36µM to >10µM. By genomic analysis, we identified 23 genes with a significant difference in AUC values between mutant and wild type cell lines, among which MUC5B mutation was found in 7/10 sensitive cell lines and only 2/10 in insensitive cell lines. Cell lines that carried MUC5B mutation had significantly lower AUC compared with MUC5B wild type cell lines (p=0.0084). Oral dosing of ATG-008, 10mg/kg, QD, induced potent tumor growth inhibition(TGI) in MUC5B mutant CDX models, with 53.2% TGI in NCI-H82 model and 81.9% TGI in SK-MES-1 model. However, in MUC5B wild type models, the TGI is only 20.5% in NCI-H209 model and 36% in NCI-H526.
 Conclusion: These results suggest that the presence of MUC5B mutation correlates with more potent anti-tumor efficacy of ATG-008, potentially serving as a positive predictive biomarker for patient enrichment that warrants further investigation in the clinic.
 Citation Format: Bing Hou, Hui Xie, Shengyue Piao, Zhi Guo, Bo Shan, Jay Mei. Identification of Muc5B mutation as a positive predictive biomarker for mTORC1/2 inhibition by ATG-008 in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4032.