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

Huo, Ku-Geng; Notsuda, Hirotsugu; Fang, Zhenhao; Liu, Ningdi Feng; Gebregiworgis, Teklab; Li, Quan; Pham, Nhu-An; Li, Ming; Liu, Geoffrey; Shepherd, Frances A.; Marshall, Christopher B.; Ikura, Mitsuhiko; Moghal, Nadeem; Tsao, Ming‐Sound

doi:10.1016/j.jtho.2021.09.008

Cited by 14 publications

(21 citation statements)

References 32 publications

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“…28 EGFR receptor tyrosine kinase inhibitor (EGFR) is a highly selective and potent small-molecule EGFR inhibitor that competitively binds to the functional domain of tyrosine kinase with ATP, inhibits autophosphorylation, blocks proliferation, and decreases invasion and metastasis of tumor cells involved in EGFR, and thus plays an anti-tumor role. 29 EGFR-TKI is effective in 70–80% advanced EGFR-sensitive mutant NSCLC patients, and PFS can reach 9–13 months. 30 However, due to tumor drug resistant gene changes, activation of downstream signaling pathways, epithelial-mesenchymal and other drug resistance pathways resulting in secondary resistance to EGFR-TKI remains a problem.…”

Section: Discussionmentioning

confidence: 99%

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Zheng

Cui

2022

Eur J Inflamm

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Objective To assess the clinical efficacy and side effects of EGFR-TKI with or without chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma. Methods A total of 103 IIIB or IV EGFR mutation-positive lung adenocarcinoma patients admitted to the oncology department of Fujian Provincial Hospital from January 2017 to October 2020 were selected. According to genetic mutation status, patients were divided into the following groups: 19del alone, 19del combined with TP53 or other co-mutations, L858R mutation alone, and L858R mutation combined with TP53 or other co-mutations. Targeted drugs or targeted drugs combined with chemotherapy were respectively administered in the four groups. In patients with simple 19 deletion, only targeted drugs with no combined therapy were applied, resulting in seven total groups. The difference between short-term treatment and long-term treatment effects and the occurrence of adverse reactions was calculated and compared. Results There was no statistical significance of difference in the incidence of adverse reactions in seven groups ( p > 0.05). The short-term disease control rate of the combination group was higher than the targeted drug group with the difference yielding statistical significance ( p < 0.001). The short-term objective response rate of the combination group was higher than the targeted drug group, also yielding statistical significance ( p < 0.001). By October 2020, the median progression-free survival (PFS) was 16 months in the EGFR-TKI-targeted combined with chemotherapy group and 10 months in the single-drug EGFR-TKI group, and the PFS time was longer in the combination group than in the single targeted drug group, the difference being statistically significant ( p = 0.001). Conclusions In the treatment of advanced lung adenocarcinoma patients with EGFR-gene sensitive mutations, compared with single EGFR-TKI-targeted therapy, EGFR-TKI-targeted drug combined chemotherapy can control the disease progression more effectively, and does not increase adverse reactions.

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Section: Discussionmentioning

confidence: 99%

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Zheng

Cui

2022

Eur J Inflamm

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“…However, the efficacy appears to be lower compared to the sensitivity of V600E mutations ( 61 ). In contrast, some other mutations (e.g., G469 mutations) are predictors of resistance to anti-BRAF therapies but sensitivity to EGFR inhibitors ( 57 , 62 , 63 ).…”

Section: Braf and Precision Medicinementioning

confidence: 99%

Tumor-Type Agnostic, Targeted Therapies: BRAF Inhibitors Join the Group

Vranić

Basu

Hall

et al. 2023

ama

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In the present review, we briefly discuss the breakthrough advances in precision medicine using a tumor-agnostic approach and focus on BRAF treatment modalities, the mechanisms of resistance and the diagnostic approach in cancers with BRAF mutations. Tumor-type agnostic drug therapies work across cancer types and present a significant novel shift in precision cancer medicine. They are the consequence of carefully designed clinical trials that showed the value of tumor biomarkers, not just in diagnosis but in therapy guidance. Six tumor-agnostic drugs (with seven indications) have been approved through October 2022 by FDA. The first tumor-agnostic treatment modality was pembrolizumab for MSI-H/dMMR solid tumors, approved in 2017. This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions.Conclusion. Precision cancer medicine has substantially improved cancer diagnostics and treatment. Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration.

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“…RAF-265 shows synergistic antitumor activity with ZSTK-474 in medullary thyroid cancer. ,− BGB-659 is able to inhibit class I and class II BRAF mutations because it can bind both monomeric BRAFs and both protomers of an RAF dimer. BGB659 showed higher activity against BRAF WT kinase. ,,, …”

Section: Current Insight Into Braf Inhibitorsmentioning

confidence: 99%

“…BGB659 showed higher activity against BRAF WT kinase. 117,136,150,151 3.4. Challenges with BRAF and Second-Generation BRAF Inhibitors.…”

Section: Second-generation Braf Inhibitors: (αC-out)mentioning

confidence: 99%

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

et al. 2023

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Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAF V600 ), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/ OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.

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

Cited by 14 publications

References 32 publications

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Tumor-Type Agnostic, Targeted Therapies: BRAF Inhibitors Join the Group

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

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