title: Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in melanoma models.
abstract: Emergence of clinical resistance to BRAF inhibitors, alone or in combination with MEK inhibitors, limits clinical responses in melanoma. Inhibiting HSP90 offers an approach to simultaneously interfere with multiple resistance mechanisms. Using the HSP90 inhibitor AT13387, which is currently in clinical trials, we investigated the potential of HSP90 inhibition to overcome or delay the emergence of resistance to these kinase inhibitors in melanoma models. In vitro, treating vemurafenib-sensitive cells (A375 or SK-MEL-28) with a combination of AT13387 and vemurafenib prevented colony growth under conditions in which vemurafenib treatment alone generated resistant colonies. In vivo, when AT13387 was combined with vemurafenib in a SK-MEL-28, vemurafenib-sensitive model, no regrowth of tumors was observed over 5 months, although 2 of 7 tumors in the vemurafenib monotherapy group relapsed in this time. Together, these data suggest that the combination of these agents can delay the emergence of resistance. Cell lines with acquired vemurafenib resistance, derived from these models (A375R and SK-MEL-28R) were also sensitive to HSP90 inhibitor treatment; key clients were depleted, apoptosis was induced, and growth in 3D culture was inhibited. Similar effects were observed in cell lines with acquired resistance to both BRAF and MEK inhibitors (SK-MEL-28RR, WM164RR, and 1205LuRR). These data suggest that treatment with an HSP90 inhibitor, such as AT13387, is a potential approach for combating resistance to BRAF and MEK inhibition in melanoma. Moreover, frontline combination of these agents with an HSP90 inhibitor could delay the emergence of resistance, providing a strong rationale for clinical investigation of such combinations in BRAF-mutated melanoma.
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Smyth
authors.affiliation: The Department of Molecular Oncology, The Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL33612, USA.
authors.forename: Kim H T
authors.initials: KHT
authors.lastname: Paraiso
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
authors.forename: Keisha
authors.initials: K
authors.lastname: Hearn
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Rodriguez-Lopez
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Munck
authors.affiliation: The Department of Molecular Oncology, The Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL33612, USA.
authors.forename: H Eirik
authors.initials: HE
authors.lastname: Haarberg
authors.affiliation: The Department of Cutaneous Oncology, The Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL33612, USA.
authors.forename: Vernon K
authors.initials: VK
authors.lastname: Sondak
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
authors.forename: Neil T
authors.initials: NT
authors.lastname: Thompson
authors.affiliation: Astex Pharmaceuticals, 4140 Dublin Blvd, Suite 200, Dublin, CA94568, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Azab
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Lyons
authors.affiliation: The Department of Molecular Oncology, The Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL33612, USA.|The Department of Cutaneous Oncology, The Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL33612, USA.
authors.forename: Keiran S M
authors.initials: KSM
authors.lastname: Smalley
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Wallis
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology*; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone