Reference Detail

Ref Type

Journal Article

PMID

(39637338)

Authors

Di Federico A, Angelicola S, Frascino M, Siracusa I, Bisanti B, Ruzzi F, Semprini MS, De Jonge H, De Giglio A, Sperandi F, Brocchi S, Melotti B, Giunchi F, Gruppioni E, Altimari A, Lollini PL, Ardizzoni A, Palladini A, Gelsomino F

Title

Clinical and Preclinical Activity of EGFR Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Harboring BRAF Class 3 Mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	8		2024 Dec	e2400240	JCO Precis Oncol

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Abstract Text

Patients with tumors harboring BRAF class 3 mutations lack targeted therapies. These mutations are characterized by low/absent BRAF kinase domain activation and are believed to amplify already active RAS signaling, potentially triggered by receptor tyrosine kinases like EGFR.Two patients with BRAF class 3-mutated metastatic non-small-cell lung cancer (NSCLC) were treated with erlotinib at our Institution after failure of standard therapies. Two cell lines were established from patients with BRAF class 3-mutated NSCLC, and their sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was assessed using EGFR-mutated, BRAF class 1 and 2-mutated, and KRAS-mutated NSCLC cell lines as controls.Patient 1, a 60-year-old male with BRAFD594N-mutated NSCLC, achieved complete response to erlotinib after progression on first- and second-line chemotherapy. Patient 2, a 60-year-old female with BRAFD594G-mutated NSCLC, achieved partial response to erlotinib after progression on first-line chemoimmunotherapy. High baseline phosphorylated EGFR values and reduced EGFR activation following erlotinib were observed in BRAF class 3-mutated and EGFR-mutated cell lines, but not in BRAF class 1-mutated, BRAF class 2-mutated, or KRAS-mutated lines. Erlotinib inhibited 2-dimensional growth in BRAF class 3-mutated cell lines (IC50 6.33 and 7.11 µM) and in the BRAF class 2-mutated cell line (IC50 5.51 µM), albeit at higher concentrations than in EGFR-mutated lines, whereas it showed no effect on BRAF class 1-mutated (IC50, >25 µM) or KRAS-mutated (IC50, >25 µM) lines. These findings were corroborated by 3-dimensional and sphere formation assays. In the Cancer Cell Line Encyclopedia, BRAF class 3-mutated NSCLC cell lines showed greater sensitivity to EGFR-TKIs compared with BRAF class 2-mutated and KRAS-mutated lines.BRAF class 3 mutations in NSCLC may identify a novel targetable population sensitive to EGFR-TKIs.

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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 D594N	lung adenocarcinoma	predicted - sensitive	Erlotinib	Case Reports/Case Series	Actionable	In a clinical case study, Tarceva (erlotinib) treatment resulted in a persistent complete response that was ongoing after 12 years in a patient with lung adenocarcinoma harboring BRAF D594N with brain and lymph node metastases (PMID: 39637338).	39637338
BRAF D594G	lung adenocarcinoma	predicted - sensitive	Osimertinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Tagrisso (osimertinib) inhibited growth of a patient-derived lung adenocarcinoma cell line harboring BRAF D594G in culture (PMID: 39637338).	39637338
BRAF G469A	lung non-small cell carcinoma	predicted - sensitive	Erlotinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tarceva (erlotinib) inhibited growth of a non-small cell lung cancer cell line harboring BRAF G469A in 2D and 3D culture (PMID: 39637338).	39637338
BRAF G469A	lung non-small cell carcinoma	predicted - sensitive	Osimertinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tagrisso (osimertinib) inhibited growth of a non-small cell lung cancer line harboring BRAF G469A in culture (PMID: 39637338).	39637338
BRAF G466V	lung non-small cell carcinoma	predicted - sensitive	Erlotinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tarceva (erlotinib) inhibited growth of a non-small cell lung cancer cell line harboring BRAF G466V in 2D and 3D culture (PMID: 39637338).	39637338
BRAF G466V	lung non-small cell carcinoma	predicted - sensitive	Osimertinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Tagrisso (osimertinib) inhibited growth of a patient-derived non-small cell lung cancer line harboring BRAF G466V in culture (PMID: 39637338).	39637338
BRAF D594G	lung adenocarcinoma	sensitive	Erlotinib	Case Reports/Case Series	Actionable	In a clinical case study, Tarceva (erlotinib) treatment resulted in a partial response with a 40% decrease in tumor lesions in a patient with lung adenocarcinoma with bone, pleural, and lymph node metastases harboring BRAF D594G, and in a preclinical analysis, Tarceva (erlotinib) inhibited the growth of a patient-derived cell line harboring BRAF D594G in 2D and 3D culture (PMID: 39637338).	39637338

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