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Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies

Carman K M Ip1, Patrick K S Ng2, Kang Jin Jeong3

  • 1Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. ckip@bsd.uchicago.edu.

Nature Communications
|November 4, 2018
PubMed

Insights

Novel platelet-derived growth factor receptor alpha (PDGFRA) mutations drive cancer progression. One mutation, PDGFRA Y288C, activates the receptor in the endoplasmic reticulum, promoting cell survival and proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genomic aberrations in platelet-derived growth factor receptor alpha (PDGFRA) are implicated in various cancers.
  • Understanding novel PDGFRA mutations is crucial for targeted cancer therapies.

Purpose of the Study:

  • To characterize 16 novel PDGFRA mutations from diverse tumor types.
  • To identify and functionally analyze previously uncharacterized activating PDGFRA mutations.

Main Methods:

  • Identification and sequencing of novel PDGFRA mutations.
  • Functional assays to assess cell survival and proliferation.
  • Analysis of receptor dimerization, phosphorylation, and downstream signaling pathways (Akt, ERK1/2, STAT3).
  • Assessment of inhibitor sensitivity.

Main Results:

  • Three novel activating PDGFRA mutations were identified, promoting cell survival and proliferation.
  • The PDGFRA Y288C extracellular domain mutation leads to endoplasmic reticulum trapping and constitutive activation.
  • PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3.
  • PDGFRA Y288C is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors.

Conclusions:

  • Aberrant glycosylation and endoplasmic reticulum trapping can activate PDGFRA.
  • PDGFRA Y288C represents a novel oncogenic driver mutation.
  • Characterizing individual mutation consequences is vital for precision medicine.

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