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MEK1/2 regulates APOBEC3B and polymerase iota-induced mutagenesis in head and neck cancer cells

Dominik Schulz1, Guido Piontek2, Ulrich M Zissler3

  • 1Department of Internal Medicine II, Klinikum Rechts der Isar Ismaninger Straße 22, Munich 81675, Germany.

American Journal of Cancer Research
|December 7, 2021
PubMed

Insights

Chemotherapy can increase cancer cells' genetic instability, leading to drug resistance. Inhibiting MEK1/2 alongside chemotherapy significantly reduces this instability in head and neck squamous cell carcinoma (HNSCC).

Area of Science:

  • Oncology
  • Cancer Biology
  • Genetics

Background:

  • Chemotherapy resistance is a major obstacle in treating metastatic cancers.
  • Tumor heterogeneity, driven by genetic instability, contributes significantly to treatment failure.
  • Understanding mechanisms of acquired resistance is crucial for improving cancer therapy.

Purpose of the Study:

  • To investigate whether chemotherapy agents induce genetic instability in head and neck squamous cell carcinoma (HNSCC).
  • To identify molecular players involved in chemotherapy-induced genetic instability.
  • To explore therapeutic strategies for controlling genetic instability during HNSCC treatment.

Main Methods:

  • Treatment of HNSCC cells with afatinib (EGFR inhibitor) or cisplatin.
  • Measurement of mutation frequency to assess genetic instability.
  • Analysis of APOBEC3B and polymerase iota expression.
  • Inhibition of MEK1/2 signaling pathway using U0126.

Main Results:

  • Afatinib and cisplatin treatments induced increased genetic instability (mutation frequency) in HNSCC cells.
  • APOBEC3B and polymerase iota were found to be upregulated following treatment.
  • Inhibition of MEK1/2 by U0126 downregulated these proteins.
  • Combined treatment with afatinib/cisplatin and U0126 significantly reduced mutation frequency.

Conclusions:

  • EGFR inhibitors and cisplatin can dynamically induce genetic instability in HNSCC.
  • APOBEC3B and polymerase iota are key mediators of this induced instability.
  • Targeting the MEK1/2 pathway offers a potential strategy to mitigate chemotherapy-induced genetic instability in HNSCC.
Keywords:
APOBEC3BHNSCCHypermutationMEK1/2mutagenesispolymerase iota

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