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Published on: December 13, 2018

Interaction between MYC and MCL1 in the genesis and outcome of non-small-cell lung cancer

Thaddeus D Allen1, Chang Qi Zhu, Kirk D Jones

  • 1G.W. Hooper Research Foundation, University of California, San Francisco, USA. Thaddeus.Allen@ucsf.edu

Cancer Research
|March 17, 2011
PubMed

Insights

MYC activation drives lung cancer, but its negative effects are overcome by MCL1. This explains how MCL1 and MYC co-overexpression predicts poor survival in non-small cell lung cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MYC has dual roles in cancer, with pro-cancer effects emerging when anti-cancer functions are inhibited.
  • Non-small cell lung cancer (NSCLC) is a common malignancy where MYC's role is complex.
  • Apoptosis is a key negative function of MYC that needs to be circumvented for tumor progression.

Purpose of the Study:

  • To identify genetic events cooperating with MYC in non-small cell lung cancer (NSCLC) development.
  • To investigate the role of MCL1 in overcoming MYC-induced apoptosis in lung cancer.
  • To re-evaluate the prognostic significance of MCL1 in human NSCLC.

Main Methods:

  • Utilized multiple mouse models of lung adenocarcinoma with MYC overexpression.
  • Introduced Kras mutations or activated RAS to study tumorigenesis.
  • Assessed the role of MCL1 in preventing apoptosis in MYC-driven lung cancer.
  • Correlated MCL1 and MYC expression with patient survival data in human NSCLC.

Main Results:

  • MYC overexpression in mouse lung cells induced adenomas and carcinomas.
  • Tumorigenesis was enhanced by Kras/RAS mutations but required additional events to bypass apoptosis.
  • MCL1 overexpression effectively circumvented MYC-induced apoptosis in experimental models.
  • MCL1 overexpression correlated with poor patient survival in NSCLC, but only when MYC was also overexpressed.

Conclusions:

  • MCL1 can block the pro-apoptotic function of MYC, facilitating NSCLC development.
  • The combined overexpression of MYC and MCL1 is a significant predictor of poor prognosis in human NSCLC.
  • These findings reconcile experimental and clinical observations regarding MYC and MCL1 in lung cancer.

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