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Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors.
Pigment Cell Melanoma Res. 2014 May; 27(3):479-84.PC

Abstract

Vemurafenib and dabrafenib block MEK-ERK1/2 signaling and cause tumor regression in the majority of advanced-stage BRAF(V600E) melanoma patients; however, acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors. Next-generation RAF inhibitors, such as PLX7904 (PB04), effectively inhibit RAF signaling in BRAF(V600E) melanoma cells without paradoxical effects in wild-type cells. Furthermore, PLX7904 blocks the growth of vemurafenib-resistant BRAF(V600E) cells that express mutant NRAS. Acquired resistance to vemurafenib and dabrafenib is also frequently driven by expression of mutation BRAF splice variants; thus, we tested the effects of PLX7904 and its clinical analog, PLX8394 (PB03), in BRAF(V600E) splice variant-mediated vemurafenib-resistant cells. We show that paradox-breaker RAF inhibitors potently block MEK-ERK1/2 signaling, G1/S cell cycle events, survival and growth of vemurafenib/PLX4720-resistant cells harboring distinct BRAF(V600E) splice variants. These data support the further investigation of paradox-breaker RAF inhibitors as a second-line treatment option for patients failing on vemurafenib or dabrafenib.

Authors+Show Affiliations

Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24422853

Citation

Basile, Kevin J., et al. "Inhibition of Mutant BRAF Splice Variant Signaling By Next-generation, Selective RAF Inhibitors." Pigment Cell & Melanoma Research, vol. 27, no. 3, 2014, pp. 479-84.
Basile KJ, Le K, Hartsough EJ, et al. Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res. 2014;27(3):479-84.
Basile, K. J., Le, K., Hartsough, E. J., & Aplin, A. E. (2014). Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell & Melanoma Research, 27(3), 479-84. https://doi.org/10.1111/pcmr.12218
Basile KJ, et al. Inhibition of Mutant BRAF Splice Variant Signaling By Next-generation, Selective RAF Inhibitors. Pigment Cell Melanoma Res. 2014;27(3):479-84. PubMed PMID: 24422853.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. AU - Basile,Kevin J, AU - Le,Kaitlyn, AU - Hartsough,Edward J, AU - Aplin,Andrew E, Y1 - 2014/02/10/ PY - 2013/09/03/received PY - 2014/01/07/accepted PY - 2014/1/16/entrez PY - 2014/1/16/pubmed PY - 2014/12/19/medline KW - BRAF KW - Paradox-breaker RAF inhibitor KW - splice variant KW - vemurafenib resistance SP - 479 EP - 84 JF - Pigment cell & melanoma research JO - Pigment Cell Melanoma Res VL - 27 IS - 3 N2 - Vemurafenib and dabrafenib block MEK-ERK1/2 signaling and cause tumor regression in the majority of advanced-stage BRAF(V600E) melanoma patients; however, acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors. Next-generation RAF inhibitors, such as PLX7904 (PB04), effectively inhibit RAF signaling in BRAF(V600E) melanoma cells without paradoxical effects in wild-type cells. Furthermore, PLX7904 blocks the growth of vemurafenib-resistant BRAF(V600E) cells that express mutant NRAS. Acquired resistance to vemurafenib and dabrafenib is also frequently driven by expression of mutation BRAF splice variants; thus, we tested the effects of PLX7904 and its clinical analog, PLX8394 (PB03), in BRAF(V600E) splice variant-mediated vemurafenib-resistant cells. We show that paradox-breaker RAF inhibitors potently block MEK-ERK1/2 signaling, G1/S cell cycle events, survival and growth of vemurafenib/PLX4720-resistant cells harboring distinct BRAF(V600E) splice variants. These data support the further investigation of paradox-breaker RAF inhibitors as a second-line treatment option for patients failing on vemurafenib or dabrafenib. SN - 1755-148X UR - https://www.unboundmedicine.com/medline/citation/24422853/Inhibition_of_mutant_BRAF_splice_variant_signaling_by_next_generation_selective_RAF_inhibitors_ L2 - https://doi.org/10.1111/pcmr.12218 DB - PRIME DP - Unbound Medicine ER -