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ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in

Jing Jin Gu1, Kevin M Scott1, Arijit Ghosh2

  • 1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.

Cell Reports
|July 16, 2026
PubMed

Insights

Inactivating ABL tyrosine kinases hinders metastatic small cell lung cancer (SCLC) growth by increasing DNA damage. Combining ABL inhibitors with ATR inhibitors synergistically kills SCLC cells, offering a potential treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with poor survival rates, often diagnosed at the metastatic stage.
  • Current treatments for metastatic SCLC have limited efficacy, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

  • To investigate the role of ABL tyrosine kinases in the progression of metastatic SCLC.
  • To explore the potential of targeting ABL kinases, alone or in combination with DNA damage-repair pathways, for SCLC treatment.

Main Methods:

  • Inactivation of ABL tyrosine kinases in SCLC models.
  • Assessment of transcription-replication conflicts (TRCs), replication fork progression, and homologous recombination protein function (RAD51, RAD52).
  • Evaluation of combination therapy with ABL inhibitors and ATR inhibitors in vitro and in vivo.

Main Results:

  • ABL inactivation impairs metastatic SCLC outgrowth and prolongs survival by increasing TRCs and compromising replication fork progression.
  • ABL kinase activity is crucial for RAD51 and RAD52 function in managing DNA damage.
  • Concurrent inactivation of ABL and ATR synergistically inhibits SCLC cell growth and metastatic outgrowth.

Conclusions:

  • ABL tyrosine kinases play a critical role in SCLC metastasis and survival.
  • Targeting ABL kinases disrupts DNA replication and repair mechanisms in SCLC.
  • Combination therapy with ABL and ATR inhibitors presents a promising strategy for treating metastatic SCLC.
Keywords:
CP: cancerCP: molecular biologyabl kinasedna damage-repairmetastasisreplication forkssmall cell lung cancertranscription-replication conflicts

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