1685P - Oncogenic activity of recurrent ERBB4 mutations and their sensitivity to neratinib

Background

Hundreds of somatic ERBB4 (HER4) mutations have been described in cancer tissues with very limited information available about their functional significance. Understanding the activity of ERBB4 mutations is needed to assess the relevance of targeting ERBB4 in human cancers with matched therapies, such as neratinib. Neratinib is an irreversible pan-ERBB tyrosine kinase inhibitor that potently inhibits ERBB4, and is currently approved for early stage and metastatic HER2+ breast cancers, and is under clinical evaluation for EGFR-, ERBB2-, and ERBB4-mutant cancers, including in the SUMMIT clinical trial (NCT01953926).

Methods

We selected 18 ERBB4 mutations (Table) from cBioPortal data using the following criteria: 1) high recurrence, 2) analogy to oncogenic mutations in other ERBB family members and/or 3) structural location suggested functional relevance. The transforming potential of the ERBB4 variants was tested by assessing 1) IL-3 independent growth of mouse lymphoid Ba/F3 cells, 2) focus formation of mouse NIH-3T3 fibroblasts, and 3) growth of human mammary epithelial MCF-10A cells.

Results

Half of the selected ERBB4 mutations demonstrated transforming potential in at least one of the models. Structural analysis suggested that the most transforming mutants (S303F, E452K, L798R) stabilize receptor dimers leading to enhanced ERBB4 activity. The most potent mutation was S303F, which is analogous to the well-known activating ERBB2 mutation S310F. To assess the predictive value of these mutations for neratinib, drug response assays are ongoing. The SUMMIT trial enrolled three patients with tumors harboring ERBB4 mutations (N465K, R544W, V840I); case details will be presented. Table: 1685P

Somatic ERBB4 mutations chosen for functional analyses

Conclusions

Several of the recurrent ERBB4 mutations are transforming. Further investigation into potential utility of clinically used pan-ERBB inhibitors, such as neratinib, for patients whose tumors harbor these ERBB4 mutations is warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Puma Biotechnology, Inc.

Disclosure

L.D. Eli: Financial Interests, Personal, Full or part-time Employment, I am a full time employee of Puma Biotechnology, Inc. Financial Interests, Personal, Stocks/Shares, I am a stakeholder in Puma Biotechnology, Inc.; Non-Financial Interests, Leadership Role, I am Vice President, Translational Medicine and Diagnostics at Puma Biotechnology, Inc. K.J. Kurppa: Non-Financial Interests, Institutional, Research Grant: Orion Pharma. K. Elenius: Financial Interests, Personal, Invited Speaker: Academy of Finland, Finnish Medical Foundation; Financial Interests, Personal, Stocks/Shares: Roche, Orion, Novo Nordisk; Financial Interests, Personal, Ownership Interest: Abomics; Financial Interests, Institutional, Funding: Puma Biotechnology. All other authors have declared no conflicts of interest.