The duality of ERBB4 function in aggressive BRAF WT Melanomas
CONCLUSIONS
- ERBB4 is mutated in a significant fraction of melanomas. These mutations do not appear to be randomly distributed, suggesting that ERBB4 mutant alleles function as tumor drivers.
- ERBB4 appears to function as a context-dependent tumor suppressor or oncoprotein in some melanoma cell lines.
- ERBB4 mutants appear to cooperate with signaling by the RAS/RAF/MAPK pathway in melanoma.
- ERBB4 mutations and BRAF V600 mutations tend to occur without the other. Therefore, they appear to independently drive tumors.
- We postulate that gain-of-function (GOF) ERBB4 mutants function as tumor drivers by potentiating signaling by ERBB4 heterodimers through the PI3K pathway.
- We postulate that loss-of-function (LOF) ERBB4 mutants function as tumor drivers by disrupting the inhibition of PI3K pathway signaling by ERBB4 homodimers.
- The ERBB4 mutations are for the most part uncharacterized. Therefore, there is a need to distinguish which ERBB4 mutations function as drivers and can serve as biomarkers for therapy.
FUTURE STUDIES
We will use Melanoma cell lines to identify GOF and LOF ERBB4 Mutations
We will express known GOF ERBB4 mutants, known LOF ERBB4 mutants, and uncharacterized ERBB4 mutants found in the TCGA-SKCM dataset in melanoma cell lines. We will evaluate the effects of these ERBB4 mutants on cell proliferation, anchorage-independence, and motility. We anticipate that we will identify GOF ERBB4 mutant alleles that stimulate the oncogenic activity of ERBB4 heterodimers and LOF ERBB4 mutant alleles that disrupt the tumor suppressor activity of ERBB4 homodimers in the context of the ERBB4 Q646C mutant.
PURPOSE
- ERBB4 encodes a receptor tyrosine kinase that is closely related to the epidermal growth factor receptor (EGFR), ERBB2 (HER2), and ERBB3 (HER3), all of which are validated targets for therapeutic intervention in numerous epithelial tumors.
- The role that ERBB4 plays in human malignancies is ambiguous, as it acts as a context-dependent oncogene AND tumor suppressor gene.
- Our in silico analysis of The Cancer Genome Atlas - Skin Cutaneous Melanoma dataset suggest that ERBB4 mutant alleles function as drivers of BRAF WT metastatic melanomas.
- Therefore, we need model systems that enable the identification of ERBB4 mutant alleles which function as tumor drivers in various cancers.
Acknowledgments and disclosures
Contact Information:
Lauren Lucas – lml0020@auburn.edu
Dr. David Riese – driese@auburn.edu
OBJECTIVE
Identify ERBB4 mutant alleles which function as tumor drivers
- Upon ligand binding, ERBB receptors can homo- or heterodimerize, resulting in dimer-specific downstream signaling events.
- ERBB4 homodimers are associated with tumor suppressor activity and ERBB4-EGFR and ERBB4-ERBB2 heterodimers are associated with oncogenic activity.
- Thus, we predict that ERBB4 tumor driver mutations will inhibit the tumor suppressor activity of ERBB4 homodimers or will stimulate the oncogenic activity of ERBB4-EGFR or ERBB4-ERBB2 heterodimers.
RESULTS
Analysis of TCGA-SKCM dataset identified ERBB4 as a putative tumor driver
- The ratio of non-synonymous missense mutations to synonymous mutations (N/S) in ERBB4 exceeds the 2.5:1 ratio indicative of driver mutations.
- The ERBB4 missense mutations found in melanoma are distributed across the entire coding sequence.
- However, simulated assignment of missense mutations across ERBB4 reveals that the observed ”hot spots” of mutations appear to be the result of selection and that ERBB4 mutations are melanoma drivers
This research has been funded by an Auburn University Research Initiative in Cancer (AURIC) fellowship to RLC, by the US Department of Education GAANN Graduate Fellowship Program in Biological & Pharmaceutical Engineering Award No. P200A120244 to Auburn University, an Auburn University Presidential Graduate Research Fellowship to LML, and other support from AURIC, the Department of Drug Discovery and Development, and the Harrison School of Pharmacy. DJR is a consultant to Eli Lilly and Bristol-Myers Squibb.
Identification of ERBB4 mutant alleles that function as tumor drivers
Lauren Lucas1, Richard Cullum1,2, Vipasha Dwivedi1, Damien Waits3, Taraswi Ghosh1, Joely Burgess1, Connor Kelley1, Elizabeth Knerr1,4, Jessica Markham1,3, Stephen Miller1, Kenneth Halanych3, Allan David2, and David J. Riese II1
Departments of 1Drug Discovery and Development, 2Chemical Engineering, and 3Biological Sciences, 4Chemistry and Biochemistry, Auburn University, Auburn, AL 36849
- Non-synonymous ERBB4 mutations have a tendency to occur in melanomas in which there is a BRAF WT genotype. This suggests that ERBB4 mutations and the BRAF V600 mutation may independently drive melanoma (P=0.1).
- Non-synonymous ERBB4 mutations preferentially occur in melanomas in which there is NO other evidence of genetic alterations that cause increased PI3K pathway signaling. This suggests that ERBB4 mutations drive tumors by causing increased signaling of the PI3K pathway (chi-squared, P=0.014).
- Non-synonymous ERBB4 mutations preferentially occur in melanomas in which there is a GOF RAS mutation or a LOF NF1 mutation. This suggests that ERBB4 mutants cooperate with RAS signaling (chi-squared, P=0.001).
ERBB4 functions as a context-dependent oncoprotein and possible tumor suppressor in some Melanoma cell lines
- WT ERBB4 appears to function an an oncogene in the MEL-JUSO and IPC-298 melanoma cell lines
- The preferentially homodimerized, ERBB4 Q646C, mutant may function as a tumor suppressor in the IPC-298 melanoma cell line
470 Melanoma Cases in TCGA-SKCM Dataset
103 Cases with ERBB4 Mutation(s)
77 Cases with Non-Synonymous Mutations
N/S = 2.9
86 Unique Non-synonymous Mutations
Vector ERBB4 WT ERBB4 Q646C
GOF ERBB4-EGFR Heterodimer
Melanoma Genesis or Progression
Abrogates need for
ERBB4/PI3K signaling?