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Ref Type

Journal Article

PMID

(20538618)

Authors

Whittaker S, Kirk R, Hayward R, Zambon A, Viros A, Cantarino N, Affolter A, Nourry A, Niculescu-Duvaz D, Springer C, Marais R

Title

Gatekeeper mutations mediate resistance to BRAF-targeted therapies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	2	35	2010 Jun 9	35ra41	Sci Transl Med

URL

Abstract Text

BRAF is a serine-threonine-specific protein kinase that is mutated in 2% of human cancers. Oncogenic BRAF is a validated therapeutic target that constitutively activates mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling, driving tumor cell proliferation and survival. Drugs designed to target BRAF have been developed, but it is difficult to prove that they mediate their antitumor effects by inhibiting BRAF rather than by working through off-target effects. We generated drug-resistant versions of oncogenic BRAF by mutating the gatekeeper residue. Signaling by the mutant proteins was resistant to the small-molecule inhibitor sorafenib, but sorafenib still inhibited the growth of tumors driven by the mutant protein. In contrast, both BRAF signaling and tumor growth were resistant to another RAF drug, PLX4720. These data provide unequivocal evidence that sorafenib mediates its antitumor effects in a manner that is independent of its ability to target oncogenic BRAF, whereas PLX4720 inhibits tumor growth by targeting oncogenic BRAF directly.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
No data available in table

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
No data available in table

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Showing 1 to 3 of 3 entries

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	T529I	missense	unknown	BRAF T529I is a gatekeeper mutation that lies within the protein kinase domain of the Braf protein (PMID: 20538618). T529I has been demonstrated to confer resistance to Raf inhibitors in the context of BRAF V600E (PMID: 20538618), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Mar 2025).	Y
BRAF	T529M	missense	unknown	BRAF T529M lies within the protein kinase domain of the Braf protein (UniProt.org). T529M has been demonstrated to confer resistance to Raf inhibitors (PMID: 20538618, PMID: 28783719, PMID: 31453322), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Sep 2024).	Y
BRAF	T529N	missense	unknown	BRAF T529N lies within the protein kinase domain of the Braf protein (UniProt.org). T529N demonstrates RAS-induced kinase activity similar to wild-type Braf in culture (PMID: 20141835), and confers resistance to Raf inhibitors (PMID: 20538618, PMID: 20807807, PMID: 20141835), but has not been fully biochemically characterized and therefore, its effect on Braf protein function is unknown.	Y

Showing 1 to 3 of 3 entries

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Showing 1 to 19 of 19 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF T529I BRAF V600E	Advanced Solid Tumor	predicted - resistant	SB590885	Preclinical	Actionable	In a preclinical study, transformed cells expressing BRAF V600E and the gatepkeeper mutation BRAF T529I were insensitive to SB590885-mediated inhibition of ERK signaling in culture (PMID: 20538618).	20538618
BRAF T529I BRAF V600E	Advanced Solid Tumor	predicted - resistant	PLX4720	Preclinical	Actionable	In a preclinical study, transformed cells expressing BRAF V600E and the gatepkeeper mutation BRAF T529I were insensitive to PLX4720-mediated inhibition of ERK signaling in culture (PMID: 20538618).	20538618
BRAF T529I BRAF V600E	Advanced Solid Tumor	predicted - sensitive	RAF265	Preclinical	Actionable	In a preclinical study, RAF265 inhibited kinase activity in vitro, and downstream Erk phosphorylation in cells expressing BRAF V600E and the gatekeeper mutation BRAF T529I to a similar degree as transformed cells expressing BRAF V600E in culture (PMID: 20538618).	20538618
BRAF T529I BRAF V600E	Advanced Solid Tumor	sensitive	CI-1040	Preclinical	Actionable	In a preclinical study, CI-1040 (PD184352) inhibited Erk phosphorylation in transformed cells expressing BRAF V600E and the gatekeeper mutation BRAF T529I in culture (PMID: 20538618).	20538618
BRAF T529I BRAF V600E	Advanced Solid Tumor	predicted - sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited kinase activity in vitro, and downstream Erk phosphorylation in cells expressing BRAF V600E and the gatekeeper mutation BRAF T529I to a similar degree as transformed cells expressing BRAF V600E in culture (PMID: 20538618).	20538618
BRAF T529M BRAF V600E	Advanced Solid Tumor	predicted - sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited kinase activity in vitro, and downstream Erk phosphorylation in cells expressing BRAF V600E and the gatekeeper mutation BRAF T529M to a similar degree as transformed cells expressing BRAF V600E in culture (PMID: 20538618).	20538618
BRAF T529M BRAF V600E	Advanced Solid Tumor	predicted - sensitive	RAF265	Preclinical	Actionable	In a preclinical study, RAF265 inhibited kinase activity in vitro, and downstream Erk phosphorylation in cells expressing BRAF V600E and the gatekeeper mutation BRAF T529M to a similar degree as transformed cells expressing BRAF V600E in culture (PMID: 20538618).	20538618
BRAF T529M BRAF V600E	Advanced Solid Tumor	predicted - resistant	SB590885	Preclinical	Actionable	In a preclinical study, transformed cells expressing BRAF V600E and the gatepkeeper mutation BRAF T529M were insensitive to SB590885-mediated inhibition of ERK signaling in culture (PMID: 20538618).	20538618
BRAF T529M BRAF V600E	Advanced Solid Tumor	predicted - resistant	PLX4720	Preclinical	Actionable	In a preclinical study, transformed cells expressing BRAF V600E and the gatepkeeper mutation BRAF T529M were insensitive to PLX4720-mediated inhibition of ERK signaling in culture (PMID: 20538618).	20538618
BRAF T529M BRAF V600E	Advanced Solid Tumor	predicted - sensitive	CI-1040	Preclinical	Actionable	In a preclinical study, CI-1040 (PD184352) inhibited Erk phosphorylation in transformed cells expressing BRAF V600E and the gatekeeper mutation BRAF T529M in culture (PMID: 20538618).	20538618
BRAF T529N BRAF V600E	Advanced Solid Tumor	sensitive	CI-1040	Preclinical	Actionable	In a preclinical study, CI-1040 (PD184352) inhibited Erk phosphorylation and growth of transformed cells expressing BRAF V600E and the gatekeeper mutation BRAF T529N in culture (PMID: 20538618).	20538618
BRAF T529N BRAF V600E	Advanced Solid Tumor	conflicting	Sorafenib	Preclinical	Actionable	In a preclinical study, transformed cells expressing BRAF V600E and the gatepkeeper mutation BRAF T529N were insensitive to Nexavar (sorafenib)-mediated inhibition of Erk phosphorylation but were equally as sensitive to Nexavar (sorafenib)-mediated growth inhibition as transformed cells expressing BRAF V600E in culture (PMID: 20538618).	20538618
BRAF T529N BRAF V600E	Advanced Solid Tumor	resistant	PLX4720	Preclinical	Actionable	In a preclinical study, transformed cells expressing BRAF V600E and the gatepkeeper mutation BRAF T529N were insensitive to PLX4720 in culture (PMID: 20538618).	20538618
BRAF T529N BRAF V600E	Advanced Solid Tumor	resistant	RAF265	Preclinical	Actionable	In a preclinical study, transformed cells expressing BRAF V600E and the gatepkeeper mutation BRAF T529N were insensitive to RAF265 in culture (PMID: 20538618).	20538618
BRAF T529N BRAF V600E	Advanced Solid Tumor	resistant	SB590885	Preclinical	Actionable	In a preclinical study, transformed cells expressing BRAF V600E and the gatepkeeper mutation BRAF T529N were insensitive to SB590885 in culture (PMID: 20538618).	20538618
BRAF V600E	Advanced Solid Tumor	sensitive	RAF265	Preclinical	Actionable	In a preclinical study, RAF265 inhibited Erk phosphorylation and cell proliferation in BRAF V600E expressing cells in culture (PMID: 20538618).	20538618
BRAF V600E	Advanced Solid Tumor	sensitive	PLX4720	Preclinical	Actionable	In a preclinical study, PLX4720 inhibited Erk phosphorylation and cell proliferation of transformed cells expression BRAF V600E in culture (PMID: 20538618).	20538618
BRAF V600E	Advanced Solid Tumor	sensitive	SB590885	Preclinical	Actionable	In a preclinical study, SB590885 inhibited inhibited Erk phosphorylation and cell proliferation of transformed cells expression BRAF V600E in culture (PMID: 20538618).	20538618
BRAF V600E	Advanced Solid Tumor	sensitive	CI-1040	Preclinical	Actionable	In a preclinical study, CI-1040 (PD184352) inhibited Erk phosphorylation and growth of transformed cells expressing BRAF V600E in culture (PMID: 20538618).	20538618

Showing 1 to 19 of 19 entries

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