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Oncogenic p53 induces mitotic errors in lung cancer cells by recopying DNA replication forks conferring targetable

Swati Palit Deb1, Shilpa Singh2, Lilia Gheghiani1

  • 1Virginia Commonwealth University.

Research Square
|August 20, 2025
PubMed

Insights

Oncogenic p53 mutations cause replication stress, leading to DNA errors and tumor growth. Targeting these errors with ATM inhibitors offers a new therapeutic strategy for lung cancer patients with p53 mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Oncogenic p53 mutations (Onc-p53) are common in lung and other solid tumors, often linked to chromosomal aberrations.
  • The mechanisms by which Onc-p53 drives chromosomal instability and its role in tumor progression are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism linking Onc-p53 to chromosomal aberrations and tumor growth.
  • To identify potential therapeutic vulnerabilities associated with Onc-p53-driven tumorigenesis.

Main Methods:

  • Investigated replication stress and DNA replication fork dynamics in cells with Onc-p53.
  • Utilized time-lapse video microscopy to observe mitotic aberrations and DNA segregation errors.
  • Employed xenograft lung tumor models with knockdown of active replication forks and ATM activation inhibitors.

Main Results:

  • Onc-p53 induces replication stress, causing DNA replication fork re-copying and subsequent mitotic aberrations and DNA segregation errors.
  • These errors activate ATM signaling, stabilizing Onc-p53 and creating a feedforward cycle that accelerates tumor formation.
  • Targeting replication forks and ATM activation synergistically induced apoptosis in lung cancer cells with Onc-p53, demonstrating therapeutic potential.

Conclusions:

  • A novel mechanism connects replication stress from Onc-p53 to its stabilization and chromosomal instability, accelerating lung cancer growth.
  • Onc-p53-induced mitotic errors represent a targetable vulnerability for developing tumor-specific therapies.
  • These findings offer a promising avenue for treating a significant proportion of cancer patients with p53 mutations.

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