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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. | ||||||||||||
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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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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 | 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 | 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 |
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 |