Ripretinib and MEK Inhibitors Synergize to Induce Apoptosis in Preclinical Models of GIST and Systemic Mastocytosis.
Animals
Apoptosis
/ drug effects
Cell Line, Tumor
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
/ genetics
Drug Synergism
Gastrointestinal Stromal Tumors
/ drug therapy
Humans
Mastocytosis, Systemic
/ drug therapy
Mice
Mitogen-Activated Protein Kinase Kinases
/ antagonists & inhibitors
Naphthyridines
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Urea
/ analogs & derivatives
Xenograft Model Antitumor Assays
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
22
09
2020
revised:
10
02
2021
accepted:
19
04
2021
pubmed:
6
5
2021
medline:
11
1
2022
entrez:
5
5
2021
Statut:
ppublish
Résumé
The majority of gastrointestinal stromal tumors (GIST) harbor constitutively activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and regorafenib are available as first-, second-, and third-line targeted therapies, respectively, for metastatic or unresectable KIT-driven GIST. Treatment of patients with GIST with KIT kinase inhibitors generally leads to a partial response or stable disease but most patients eventually progress by developing secondary resistance mutations in KIT. Tumor heterogeneity for secondary resistant KIT mutations within the same patient adds further complexity to GIST treatment. Several other mechanisms converge and reactivate the MAPK pathway upon KIT/PDGFRA-targeted inhibition, generating treatment adaptation and impairing cytotoxicity. To address the multiple potential pathways of drug resistance in GIST, the KIT/PDGFRA inhibitor ripretinib was combined with MEK inhibitors in cell lines and mouse models. Ripretinib potently inhibits a broad spectrum of primary and drug-resistant KIT/PDGFRA mutants and is approved by the FDA for the treatment of adult patients with advanced GIST who have received previous treatment with 3 or more kinase inhibitors, including imatinib. Here we show that ripretinib treatment in combination with MEK inhibitors is effective at inducing and enhancing the apoptotic response and preventing growth of resistant colonies in both imatinib-sensitive and -resistant GIST cell lines, even after long-term removal of drugs. The effect was also observed in systemic mastocytosis (SM) cells, wherein the primary drug-resistant KIT D816V is the driver mutation. Our results show that the combination of KIT and MEK inhibition has the potential to induce cytocidal responses in GIST and SM cells.
Identifiants
pubmed: 33947686
pii: 1535-7163.MCT-20-0824
doi: 10.1158/1535-7163.MCT-20-0824
doi:
Substances chimiques
Naphthyridines
0
Protein Kinase Inhibitors
0
Urea
8W8T17847W
ripretinib
9XW757O13D
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1234-1245Informations de copyright
©2021 American Association for Cancer Research.
Références
Ducimetiere F, Lurkin A, Ranchere-Vince D, Decouvelaere AV, Peoc'h M, Istier L, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6:e20294.
Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342–9.
Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet. 2007;369:1731–41.
Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–5.
Bachet JB, Hostein I, Cesne AL, Brahimi S, Beauchet A, Tabone-Eglinger S, et al. Prognosis and predictive value of KIT exon 11 deletion in GISTs. Br J Cancer. 2009;101:7–11.
Blay JY, Cesne AL, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the french sarcoma group. J Clin Oncol. 2007;25:1107–13.
Casali PG, Zalcberg J, Cesne AL, Reichardt P, Blay JY, Lindner LH, et al. Ten-Year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the european organisation for research and treatment of cancer, italian sarcoma group, and australasian gastrointestinal trials group intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol. 2017;35:1713–20.
Agaram NP, Besmer P, Wong GC, Guo T, Socci ND, Maki RG, et al. Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res. 2007;13:170–81.
Boichuk S, Parry JA, Makielski KR, Litovchick L, Baron JL, Zewe JP, et al. The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis. Cancer Res. 2013;73:5120–9.
Gupta A, Roy S, Lazar AJ, Wang WL, McAuliffe JC, Reynoso D, et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci U S A. 2010;107:14333–8.
Gajiwala KS, Wu JC, Christensen J, Deshmukh GD, Diehl W, DiNitto JP, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc Natl Acad Sci U S A. 2009;106:1542–7.
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295–302.
Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764–74.
Serrano C, Marino-Enriquez A, Tao DL, Ketzer J, Eilers G, Zhu M, et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 2019;120:612–20.
Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26:5352–9.
Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216:64–74.
Li B, Garcia CS, Marino-Enriquez A, Grunewald S, Wang Y, Bahri N, et al. Conjoined hyperactivation of the RAS and PI3K pathways in advanced GIST. 2016.
Muhlenberg T, Ketzer J, Heinrich MC, Grunewald S, Marino-Enriquez A, Trautmann M, et al. KIT-Dependent and KIT-Independent genomic heterogeneity of resistance in gastrointestinal stromal tumors - TORC1/2 inhibition as salvage strategy. Mol Cancer Ther. 2019;18:1985–96.
Serrano C, Wang Y, Marino-Enriquez A, Lee JC, Ravegnini G, Morgan JA, et al. KRAS and KIT gatekeeper mutations confer polyclonal primary imatinib resistance in GI stromal tumors: relevance of concomitant phosphatidylinositol 3-kinase/AKT dysregulation. J Clin Oncol. 2015;33:e93–6.
Boichuk S, Galembikova A, Dunaev P, Valeeva E, Shagimardanova E, Gusev O, et al. A novel receptor tyrosine kinase switch promotes gastrointestinal stromal tumor drug resistance. Molecules. 2017;22:2152.
Ran L, Sirota I, Cao Z, Murphy D, Chen Y, Shukla S, et al. Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth. Cancer Discov. 2015;5:304–15.
Smith BD, Kaufman MD, Lu WP, Gupta A, Leary CB, Wise SC, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35:738–51.
Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:923–34.
Dhillon S. Ripretinib: First Approval. Drugs. 2020;80:1133–8.
Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, et al. Correlation of kinase genotype and clinical outcome in the north american intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008;26:5360–7.
Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the spanish network on mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108:2366–72.
Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 1993;92:1736–44.
Pardanani A. Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management. Am J Hematol. 2019;94:363–77.
Wilson TM, Maric I, Simakova O, Bai Y, Chan EC, Olivares N, et al. Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis. Haematologica. 2011;96:459–63.
Liu Y, Tseng M, Perdreau SA, Rossi F, Antonescu C, Besmer P, et al. Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate. Cancer Res. 2007;67:2685–92.
Bardsley MR, Horvath VJ, Asuzu DT, Lorincz A, Redelman D, Hayashi Y, et al. Kitlow stem cells cause resistance to kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors. Gastroenterology. 2010;139:942–52.
Mavroeidis L, Metaxa-Mariatou V, Papoudou-Bai A, Lampraki AM, Kostadima L, Tsinokou I, et al. Comprehensive molecular screening by next generation sequencing reveals a distinctive mutational profile of KIT/PDGFRA genes and novel genomic alterations: results from a 20-year cohort of patients with GIST from north-western greece. ESMO Open. 2018;3:e000335.
Hechtman JF, Zehir A, Mitchell T, Borsu L, Singer S, Tap W, et al. Novel oncogene and tumor suppressor mutations in KIT and PDGFRA wild type gastrointestinal stromal tumors revealed by next generation sequencing. Genes Chromosomes Cancer. 2015;54:177–84.
Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008;47:853–9.
Miranda C, Nucifora M, Molinari F, Conca E, Anania MC, Bordoni A, et al. KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clin Cancer Res. 2012;18:1769–76.
Gao J, Li J, Li Y, Li Z, Gong J, Wu J, et al. Intratumoral KIT mutational heterogeneity and recurrent KIT/PDGFRA mutations in KIT/PDGFRA wild-type gastrointestinal stromal tumors. Oncotarget. 2016;7:30241–9.
Javidi-Sharifi N, Traer E, Martinez J, Gupta A, Taguchi T, Dunlap J, et al. Crosstalk between KIT and FGFR3 promotes gastrointestinal stromal tumor cell growth and drug resistance. Cancer Res. 2015;75:880–91.
Boichuk S, Galembikova A, Dunaev P, Micheeva E, Valeeva E, Novikova M, et al. Targeting of FGF-signaling re-sensitizes gastrointestinal stromal tumors (GIST) to imatinib in vitro and in vivo. Molecules. 2018;23:2643.
Hayashi Y, Bardsley MR, Toyomasu Y, Milosavljevic S, Gajdos GB, Choi KM, et al. Platelet-derived growth factor receptor-alpha regulates proliferation of gastrointestinal stromal tumor cells with mutations in KIT by stabilizing ETV1. Gastroenterology. 2015;149:420–32.
Duensing A. Targeting ETV1 in gastrointestinal stromal tumors: tripping the circuit breaker in GIST?. Cancer Discov. 2015;5:231–3.
Rosenbaum E, Kelly C, D'Angelo SP, Dickson MA, Gounder M, Keohan ML, et al. A phase I study of binimetinib (MEK162) combined with pexidartinib (PLX3397) in patients with advanced gastrointestinal stromal tumor. Oncologist. 2019;24:1309–e983.
Pierotti MA, Tamborini E, Negri T, Pricl S, Pilotti S. Targeted therapy in GIST: in silico modeling for prediction of resistance. Nat Rev Clin Oncol. 2011;8:161–70.
Jawhar M, Schwaab J, Naumann N, Horny HP, Sotlar K, Haferlach T, et al. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood. 2017;130:137–45.
Zorzan E, Hanssens K, Giantin M, Dacasto M, Dubreuil P. Mutational hotspot of TET2, IDH1, IDH2, SRSF2, SF3B1, KRAS, and NRAS from human systemic mastocytosis are not conserved in canine mast cell tumors. PLoS One. 2015;10:e0142450.
Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol. 2015;7:122–36.
Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773–81.