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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
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Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations

Kanika Bajaj Pahuja1, Thong T Nguyen1, Bijay S Jaiswal1

  • 1Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA.

Cancer Cell
|November 20, 2018
PubMed

Insights

New HER2 (human epidermal growth factor receptor 2) mutations in the transmembrane (TMD) and juxtamembrane (JMD) domains were discovered. These HER2 mutations are targetable with existing therapies, showing promise for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Deregulated human epidermal growth factor receptor 2 (HER2) signaling drives various cancers.
  • HER2 is a validated therapeutic target for numerous approved anti-cancer drugs.

Purpose of the Study:

  • To identify and characterize novel activating mutations in the HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD).
  • To investigate the functional mechanisms of these HER2 mutations and their response to targeted therapies.

Main Methods:

  • Analysis of 111,176 patient tumors to identify recurrent HER2 mutations.
  • Saturation mutagenesis screening and testing of patient-derived mutations.
  • Structural modeling and biochemical assays to determine the mechanism of activation.
  • Evaluation of patient-derived HER2 mutants against anti-HER2 antibodies and kinase inhibitors.

Main Results:

  • Recurrent activating mutations in HER2 TMD and JMD, including G660D, R678Q, E693K, and Q709L, were identified.
  • These mutations enhance HER2 activity by improving dimer interfaces or stabilizing activating conformations.
  • The G660D mutation specifically utilizes asymmetric kinase dimerization for activation.
  • Both anti-HER2 antibodies and small-molecule kinase inhibitors effectively inhibited the activity of these novel HER2 mutants.
  • A patient with germline HER2 G660D-mutant lung cancer exhibited a significant clinical response to HER2-targeted therapy.

Conclusions:

  • Novel activating mutations in the HER2 TMD/JMD represent a new class of oncogenic drivers.
  • These mutations remain susceptible to established HER2-targeted therapies, including antibodies and kinase inhibitors.
  • Targeting these specific HER2 mutations offers a promising therapeutic strategy for a subset of cancer patients.
Keywords:
ERBB2 activationERBB2 structureERBB2/HER2HER2 germline mutationHER2 kinase inhibitorsHER2 somatic mutationanti-HER2 antibodiesjuxtamembrane (JMD) domain mutationtransmembrane domain (TMD) mutation

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