Reference Detail

Ref Type

Journal Article

PMID

(34648945)

Authors

Huo KG, Notsuda H, Fang Z, Liu NF, Gebregiworgis T, Li Q, Pham NA, Li M, Liu N, Shepherd FA, Marshall CB, Ikura M, Moghal N, Tsao MS

Title

Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer	17	2	2022 Feb	277-288	J Thorac Oncol

URL

Abstract Text

Mutations in BRAF occur in 2% to 4% of patients with lung adenocarcinoma. Combination dabrafenib and trametinib, or single-agent vemurafenib is approved only for patients with cancers driven by the V600E BRAF mutation. Targeted therapy is not currently available for patients harboring non-V600 BRAF mutations.A lung adenocarcinoma patient-derived xenograft model (PHLC12) with wild-type and nonamplified EGFR was tested for response to EGFR tyrosine kinase inhibitors (TKIs). A cell line derived from this model (X12CL) was also used to evaluate drug sensitivity and to identify potential drivers by small interfering RNA knockdown. Kinase assays were used to test direct targeting of the candidate driver by the EGFR TKIs. Structural modeling including, molecular dynamics simulations, and binding assays were conducted to explore the mechanism of off-target inhibition by EGFR TKIs on the model 12 driver.Both patient-derived xenograft PHLC12 and the X12CL cell line were sensitive to multiple EGFR TKIs. The BRAFG469V mutation was found to be the only known oncogenic mutation in this model. Small interfering RNA knockdown of BRAF, but not the EGFR, killed X12CL, confirming BRAFG469V as the oncogenic driver. Kinase activity of the BRAF protein isolated from X12CL was inhibited by treatment with the EGFR TKIs gefitinib and osimertinib, and expression of BRAFG469V in non-EGFR-expressing NR6 cells promoted growth in low serum condition, which was also sensitive to EGFR TKIs. Structural modeling, molecular dynamic simulations, and in vitro binding assays support BRAFG469V being a direct target of the TKIs.Clinically approved EGFR TKIs can be repurposed to treat patients with non-small cell lung cancer harboring the BRAFG469V mutation.

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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 G469V	lung adenocarcinoma	sensitive	Afatinib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Gilotrif (afatinib) treatment inhibited viability of cells derived from a patient-derived xenograft (PDX) model of lung adenocarcinoma harboring BRAF G469V in culture and led to inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 34648945).	34648945
BRAF G469V	lung adenocarcinoma	sensitive	Osimertinib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Tagrisso (osimertinib) treatment inhibited viability of cells derived from a patient-derived xenograft (PDX) model of lung adenocarcinoma harboring BRAF G469V in culture and led to inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 34648945).	34648945
BRAF G469V	lung adenocarcinoma	sensitive	Gefitinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Iressa (gefitinib) treatment inhibited viability of cells derived from a patient-derived xenograft (PDX) model of lung adenocarcinoma harboring BRAF G469V in culture and led to inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 34648945).	34648945