Regulation and therapeutic targeting of MTHFD2 and EZH2 in KRAS mutated human pulmonary adenocarcinoma

by Yuchan Li
Doctoral thesis
Date of Examination:2023-07-26
Date of issue:2023-07-17
Advisor:Prof. Dr. Philipp Ströbel
Referee:Prof. Dr. Philipp Ströbel
Referee:Prof. Dr. Dieter Kube
Persistent Address: http://dx.doi.org/10.53846/goediss-10013

 

 

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Abstract

English

With nearly 40 %, pulmonary adenocarcinomas are the main subgroup of non-small cell lung cancers. Activating KRAS mutations occur in about 30 % of pulmonary adenocarcinoma cases and the discovery of the G12C KRAS mutation-specific inhibitor Sotorasib has considerably improved patient prognosis. Despite the specificity, about 60 % of the patients carrying the G12C KRAS mutation are resistant to Sotorasib and different mutations still cannot be targeted. However, aberrant KRAS activity is also known to dysregulate one-carbon metabolism and epigenetic regulation. Though the mechanisms behind them are largely unknown, deciphering the interplay might lead to alternative and combinatorial treatments in KRAS aberrant and Sotorasib resistant patients. This thesis aimed to investigate the one-carbon metabolism factor MTHFD2 and the epigenetic regulator EZH2 in the context of KRAS exon 2 mutations in a cohort of pulmonary adenocarcinoma tissue samples and four pulmonary adenocarcinoma cell lines. We observed a KRAS mutation-dependent expression and prognostic relevance of MTHFD2 and EZH2 in pulmonary adenocarcinomas. In cell lines, an aberrant KRAS activity generated a vulnerability towards the MTHFD2 inhibitor DS18561882 and the EZH2 inhibitor GSK126. We found that combinational treatment with DS18561882 and GSK126 is synergistic and as effective as Sotorasib alone. The metabolic inhibitor pemetrexed in combination with DS18561882 or GSK126 also showed good activity in the G12C KRAS mutated cell lines and pemetrexed together with AMG510 even doubled the response. These observations open additional and alternative treatment combinations of aberrant KRAS-activated pulmonary adenocarcinomas.
Keywords: one-carbon metabolism; MTHFD2; KRAS; EZH2; pulmonary adenocarcinoma
Schlagwörter: one-carbon metabolism; MTHFD2; KRAS; EZH2; pulmonary adenocarcinoma
 
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