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Loss-of-function screen in rhabdomyosarcoma identifies CRKL-YES as a critical signal for tumor growth

C L Yeung1, V N Ngo, P J Grohar

  • 1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Oncogene
|January 16, 2013
PubMed

Insights

CRKL protein is essential for rhabdomyosarcoma (RMS) growth. Inhibiting SRC family kinases, which CRKL signals through, suppressed RMS cell proliferation, suggesting a new therapeutic target for this pediatric cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer.
  • Novel signaling pathways driving RMS survival remain to be fully elucidated.

Purpose of the Study:

  • To identify novel signaling pathways critical for RMS survival.
  • To explore CRKL as a potential therapeutic target in RMS.

Main Methods:

  • Conducted a loss-of-function screen using an inducible small hairpin RNA (shRNA) library in RMS cell lines.
  • Assessed CRKL expression and its interaction with tyrosine kinase receptor pathways.
  • Investigated the role of SRC family kinase (SFK) signaling in RMS growth.
  • Evaluated the efficacy of SFK inhibitors (dasatinib, sarcatinib) on RMS cell proliferation.

Main Results:

  • CRKL expression is necessary for both alveolar and embryonal RMS growth in vitro and in vivo.
  • CRKL is highly expressed in RMS cell lines and tumor tissues.
  • CRKL signaling is associated with YES kinase within the SRC family kinase (SFK) pathway.
  • Inhibition of SFK signaling significantly suppressed RMS cell growth.

Conclusions:

  • CRKL is a novel, critical component of RMS growth signaling.
  • Targeting CRKL-associated SFK signaling presents a potential therapeutic strategy for RMS.
  • Functional screening is a valuable approach for identifying new therapeutic targets in aggressive pediatric cancers.

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