�ERBB4 is a Driver of BRAF WT Melanoma��Lauren Lucas�Advisor: Dr. David Riese II�3/28/2022�

1

Melanoma

• When identified at a localized stage, melanoma is easily treatable and has a 99% survival rate
• Once melanoma becomes metastatic, there is a 15-20% survival rate
• There is a need to identify treatment strategies for patients with metastatic melanoma
• Cancers are commonly segregated by alterations which cause increased aggressiveness called drivers. These drivers may be therapeutic targets – inhibiting these targets may be therapeutically effective

​

2

BRAF in Melanoma

• BRAF is a well-known driver of melanomas and the BRAF V600X mutations are found in ~50% of melanomas and confer responsiveness to BRAF and MEK inhibitors.
• BRAF WT melanomas do not respond to targeted therapeutics, yet frequently possess gain-of-function RAS or loss-of-function NF1 mutations.
• The Cancer Genome Atlas – Skin Cutaneous Melanoma (TCGA-SKCM) is a repository of cancer patient data

BRAF WT tumors are not associated with more favorable outcomes than BRAF V600X tumors, making BRAF WT melanomas a significant clinical challenge.

​

3

Is Elevated ERBB4 Signaling Oncogenic in BRAF WT Melanoma Cell Lines?

• ERBB4 encodes an ERBB family receptor tyrosine kinase
• Some ERBB4 mutants appear to be oncogenic in BRAF V600X melanomas. However, ERBB4 function in BRAF WT melanomas has not been studied
• ERBB4-EGFR or ERBB4-ERBB2 heterodimers stimulate the proliferation of numerous epithelial tumor cell lines

4

We postulate that elevated ERBB4 expression can substitute for other apparent causes of elevated PI3K signaling

5

Elevated ERBB4 expression is more likely to occur in cases where there is a RAS or NF1 mutant and no other apparent cause of increased PI3K signaling.�

6

Therefore, elevated ERBB4 signaling appears to drive BRAF WT melanomas by stimulating PI3K pathway signaling and cooperating with elevated RAS signaling

​

It appears that elevated ERBB4 signaling can substitute for other apparent causes of elevated PI3K signaling

7

We postulate that elevated ERBB4 signaling will drive malignant phenotypes in BRAF WT melanoma cell lines

Elevated ERBB4 Signaling Drives Proliferation of BRAF WT Melanoma Cell Lines�

• ERBB4 is both sufficient and necessary for clonogenic proliferation in some BRAF WT melanoma cell lines

​

8

What About ERBB4 Mutants?

• Elevated ERBB4 signaling due to increased ERBB4 expression is oncogenic in BRAF WT melanoma cell lines
• ERBB4 mutations may also cause elevated ERBB4 signaling.

9

ERBB4 missense mutations are more likely to occur in cases where there is RAS or NF1 mutant and no other apparent cause of increased PI3K signaling.�

10

Therefore, ERBB4 mutants appear to drive BRAF WT melanomas by stimulating PI3K pathway signaling and cooperating with elevated RAS signaling

It appears that ERBB4 Mutations can substitute for other apparent causes of elevated PI3K signaling

• Do 9 ERBB4 mutants prioritized from the TCGA-SKCM dataset function as tumor drivers?

11

Conclusion: ERBB4-dependent melanomas are a novel class of potentially treatable tumors

1. WT ERBB4 does indeed function as a driver of some BRAF WT melanoma cell lines.

12

PTEN

*

*

*

Ligand

2. ERBB4 oncogenic activity appears to cooperate with elevated RAS signaling by stimulating the PI3K/Akt canonical pathway.

3. ERBB4 mutants also appear to function as tumor drivers of some BRAF WT melanoma cell lines.

​

Therefore, some BRAF WT melanoma patients may be effectively treated with an inhibitor of ERBB4 heterodimerization in combination with a RAS inhibitor

Future Directions:

• Evaluate potential effectiveness of the treatment of ERBB4-dependent melanomas with putative targeted therapeutics
• Identify additional requirements for ERBB4-dependent melanomas:
• Determine whether EGFR-ERBB4 and ERBB2-ERBB4 heterodimers drive BRAF WT melanomas.
• Determine whether endogenous ERBB4 agonists are required for ERBB4 to drive BRAF WT melanoma cell lines.

13

Thank you!

Advisor: Dr. David Riese II

Graduate Students:

Vipasha Dwivedi

Rania Mohammedelhassan

​

PharmD Students/Undergraduates:

Elizabeth Knerr

Jessica Markham

Connor Kelley

14