Drug Information

Drug (ID: DG01738) and It's Reported Resistant Information

• Name: Dabrafenib/Trametinib
• Synonyms: Dabrafenib/Trametinib
• Target: .; NOUNIPROTAC; [1]

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Brain; N.A.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Pleomorphic xanthoastrocytoma [ICD-11: 2A00.0Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• In Vitro Model: Brain; N.A.

Colorectal cancer [ICD-11: 2B91]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [4]

• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colorectum; N.A.
• In Vivo Model: Patient-Derived xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Reverse-phase protein array (RPPA) analysis; Targeted next-generation sequencing (NGS) assay
• Experiment for Drug Resistance: Immunohistochemistry assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [4]

• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colorectum; N.A.
• In Vivo Model: Patient-Derived xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Reverse-phase protein array (RPPA) analysis; Targeted next-generation sequencing (NGS) assay
• Experiment for Drug Resistance: Immunohistochemistry assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [5]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data

Liver cancer [ICD-11: 2C12]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [6]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Identified from the Human Clinical Data

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [7]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [8]

• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The ERK pathway is the major deregulated pathway associated with BRAF-mutated cancers. ERK pathway inhibition has been shown to have anti-proliferative effects in cells harboring both kinase-activating and impairing BRAF mutations. The combination of Trametinib and Dabrafenib leads to more prolonged ERK inhibition and has anti-proliferative and pro-apoptotic effects in cells harboring both types of non-V600 BRAF mutations.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [10]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [11]

• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [11]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [12]

• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [13]

• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Thyroid cancer [ICD-11: 2D10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [14]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Experimental Note: Identified from the Human Clinical Data

Neuroendocrine carcinoma [ICD-11: 2D4Y]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]

• Molecule Alteration: Missense mutation; p.V600E (c.1406G>C)
• Sensitive Disease: Metastatic neuroendocrine carcinoma [ICD-11: 2D4Y.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [15]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Metastatic neuroendocrine carcinoma [ICD-11: 2D4Y.0]
• Experimental Note: Identified from the Human Clinical Data

Salivary gland carcinoma [ICD-11: 2E60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [16]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Salivary gland adenoid cystic carcinoma [ICD-11: 2E60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human laryngeal cells isolates; N.A.
• Experiment for Molecule Alteration: ctDNA sequencing assay

References

• Ref 1: Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-upAnn Oncol. 2018 Oct 1;29(Suppl 4):iv192-iv237. doi: 10.1093/annonc/mdy275.
• Ref 2: Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain TumorsJ Natl Compr Canc Netw. 2018 Apr;16(4):343-347. doi: 10.6004/jnccn.2017.7052.
• Ref 3: Targeted MAPK Pathway Inhibitors in Patients With Disseminated Pilocytic AstrocytomasJ Natl Compr Canc Netw. 2017 Aug;15(8):978-982. doi: 10.6004/jnccn.2017.0139.
• Ref 4: Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal CancerJ Clin Oncol. 2015 Dec 1;33(34):4023-31. doi: 10.1200/JCO.2015.63.2471. Epub 2015 Sep 21.
• Ref 5: Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC).
• Ref 6: Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesionJ Gastrointest Oncol. 2017 Apr;8(2):E32-E38. doi: 10.21037/jgo.2017.01.06.
• Ref 7: Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trialLancet Oncol. 2017 Oct;18(10):1307-1316. doi: 10.1016/S1470-2045(17)30679-4. Epub 2017 Sep 11.
• Ref 8: Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and DabrafenibOncotarget. 2016 Aug 26;8(36):60094-60108. doi: 10.18632/oncotarget.11635. eCollection 2017 Sep 1.
• Ref 9: Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trialLancet Oncol. 2016 Jul;17(7):984-993. doi: 10.1016/S1470-2045(16)30146-2. Epub 2016 Jun 6.
• Ref 10: Improved survival with MEK inhibition in BRAF-mutated melanomaN Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4.
• Ref 11: U.S. Food and Drug Administration.
• Ref 12: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutationsN Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29.
• Ref 13: Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With TrametinibJ Clin Oncol. 2016 Mar 10;34(8):871-8. doi: 10.1200/JCO.2015.62.9345. Epub 2016 Jan 25.
• Ref 14: KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid CancerJ Natl Compr Canc Netw. 2019 May 1;17(5):409-413. doi: 10.6004/jnccn.2019.7292.
• Ref 15: BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination TherapyCancer Discov. 2016 Jun;6(6):594-600. doi: 10.1158/2159-8290.CD-15-1192. Epub 2016 Apr 5.
• Ref 16: First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma With Combined BRAF and MEK InhibitionJ Natl Compr Canc Netw. 2018 Oct;16(10):1166-1170. doi: 10.6004/jnccn.2018.7056.