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Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma

Yuchan Li1, Omar Elakad1,2, Sha Yao1,3

  • 1Institute of Pathology, University Medical Center, 37075 Göttingen, Germany.

Metabolites
|July 27, 2022
PubMed

Insights

Targeting KRAS G12C mutations in non-small cell lung cancer (NSCLC) shows promise, but new strategies are needed. This study reveals that inhibiting Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and Enhancer of Zeste Homolog 2 (EZH2) alongside KRAS G12C improves outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Activating KRAS mutations are prevalent in pulmonary adenocarcinoma (AC), a subtype of non-small cell lung cancer (NSCLC).
  • Targeted therapies for KRAS G12C mutations have improved prognosis, but response rates are limited, and other KRAS mutations remain untargetable.
  • Dysregulation of one-carbon metabolism (1CM) and epigenetic processes by KRAS is known, yet their therapeutic potential in combination treatments is underexplored.

Purpose of the Study:

  • To investigate the dependency of Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and Enhancer of Zeste Homolog 2 (EZH2) expression on activated KRAS in AC.
  • To evaluate the prognostic relevance of MTHFD2 and EZH2 in KRAS-mutated AC.
  • To explore the therapeutic potential of co-inhibiting MTHFD2 and EZH2 in NSCLC.

Main Methods:

  • Analysis of MTHFD2 and EZH2 expression in relation to KRAS mutations in AC.
  • Assessment of cancer cell line vulnerability to MTHFD2 and EZH2 inhibitors under aberrant KRAS activity.
  • Evaluation of synergistic effects of co-inhibiting MTHFD2 and EZH2, and comparison with KRASG12C inhibition.

Main Results:

  • MTHFD2 and EZH2 expression are directly dependent on mutationally activated KRAS in AC.
  • Aberrant KRAS activity creates a vulnerability in AC cell lines to MTHFD2 and EZH2 inhibitors.
  • Co-inhibition of MTHFD2 and EZH2 demonstrates synergistic efficacy, comparable to KRASG12C inhibition alone.

Conclusions:

  • MTHFD2 and EZH2 are key downstream effectors of oncogenic KRAS in AC, with significant prognostic implications.
  • Targeting MTHFD2 and EZH2 represents a promising therapeutic strategy for KRAS-mutated NSCLC.
  • Combined inhibition of MTHFD2 and EZH2 offers a potential approach to overcome resistance and improve patient outcomes in NSCLC.
Keywords:
EZH2KRASMTHFD2one-carbon metabolismpulmonary adenocarcinoma

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