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RET rearrangements are actionable alterations in breast cancer

Bhavna S Paratala1,2, Jon H Chung3, Casey B Williams4

  • 1Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.

Nature Communications
|November 18, 2018
PubMed

Insights

RET gene alterations, including fusions and amplification, are found in breast cancer. These alterations can be targeted with RET inhibitors, showing promise for treating certain breast cancer patients.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • The oncogenic RET gene is implicated in thyroid and lung cancers.
  • RET gene alterations, such as fusions, are not well-characterized in breast cancer.

Purpose of the Study:

  • To investigate the frequency, oncogenic potential, and therapeutic actionability of RET gene alterations in breast cancer.
  • To functionally characterize identified RET alterations and their downstream signaling pathways.

Main Methods:

  • Genomic profiling to identify RET alterations (amplification, missense mutations, fusions, rearrangements).
  • Functional characterization of RET fusions and amplification using cell transformation and xenograft models.
  • Assessment of sensitivity to RET inhibition.

Main Results:

  • RET alterations, including fusions and amplification, were identified in a subset of breast cancers.
  • Characterized RET alterations activated RET kinase, driving MAPK and PI3K signaling.
  • These alterations induced cell transformation, supported tumor formation, and were actionable with RET inhibitors.
  • A patient with metastatic breast cancer showed a clinical response to a RET inhibitor after progression on HER2-targeted therapy.

Conclusions:

  • RET gene alterations represent a novel targetable vulnerability in a subset of breast cancers.
  • Genomic profiling can identify patients who may benefit from RET-targeted therapies.

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