Reference Detail

Ref Type

Journal Article

PMID

(38854737)

Authors

DuBose E, Bevill SM, Mitchell DK, Sciaky N, Golitz BT, Dixon SAH, Rhodes SD, Bear JE, Johnson GL, Angus SP

Title

Neratinib, a pan ERBB/HER inhibitor, restores sensitivity of PTEN-null, BRAFV600E melanoma to BRAF/MEK inhibition.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Frontiers in oncology	14		2024	1191217	Front Oncol

URL

Abstract Text

Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss-of-function mutations occur in ~40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy.To compare the response of PTEN null to PTEN wild-type cells in an isogenic background, CRISPR/Cas9 was used to knock out PTEN in a melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing, functional kinome analysis, and drug synergy screening were employed in the context of BRAF/MEK inhibition.RNA sequencing and functional kinome analysis revealed that the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAF and MEK1/2 in PTEN null, BRAFV600E cells dramatically induced the expression of ERBB3/HER3 relative to wild-type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with BRAFi/MEKi revealed that the pan ERBB/HER inhibitor, neratinib, could reverse the resistance observed in PTEN null, BRAFV600E cells.The findings indicate that PTEN null BRAFV600E melanoma exhibits increased reliance on ERBB/HER signaling when treated with clinically approved BRAFi/MEKi combinations. Future studies are warranted to test neratinib reversal of BRAFi/MEKi resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E PTEN del	melanoma	sensitive	Dabrafenib + Neratinib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Nerlynx (neratinib) restored sensitivity to Tafinlar (dabrafenib) and Mekinist (trametinib) and led to synergistic inhibition of a melanoma cell line harboring BRAF V600E and engineered via CRISPR-Cas9 to harbor a PTEN knockout in culture (PMID: 38854737).	38854737
BRAF V600E PTEN del	melanoma	decreased response	Dabrafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF V600E and engineered via CRISPR-Cas9 to harbor a PTEN knockout demonstrated decreased sensitivity to treatment with Tafinlar (dabrafenib) and Mekinist (trametinib) compared to cells with wild-type PTEN in culture (PMID: 38854737).	38854737
BRAF V600E PTEN del	melanoma	decreased response	Cobimetinib + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF V600E and engineered via CRISPR-Cas9 to harbor a PTEN knockout demonstrated decreased sensitivity to treatment with Cotellic (cobimetinib) and Zelboraf (vemurafenib) compared to cells with wild-type PTEN in culture (PMID: 38854737).	38854737
BRAF V600E PTEN del	melanoma	sensitive	Afatinib + Dabrafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Gilotrif (afatinib) restored sensitivity to Tafinlar (dabrafenib) and Mekinist (trametinib) and led to synergistic inhibition of a melanoma cell line harboring BRAF V600E and engineered via CRISPR-Cas9 to harbor a PTEN knockout in culture (PMID: 38854737).	38854737
BRAF V600E PTEN del	melanoma	decreased response	Binimetinib + Encorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF V600E and engineered via CRISPR-Cas9 to harbor a PTEN knockout demonstrated decreased sensitivity to treatment with Mektovi (binimetinib) and Braftovi (encorafenib) compared to cells with wild-type PTEN in culture (PMID: 38854737).	38854737