Concomitant inhibition of PI3Kb and BRAF or MEK in PTEN-Deficient/BRAF-Mutant melanoma treatment: Preclinical assessment of SAR260301 oral PI3Kβ-Selective inhibitor

Molecular Cancer Therapeutics

Volumn 15, Issue 7, 2016, Pages 1460-1471

  Bonnevaux, Helene ^a   Lemaitre, Olivier ^a   Vincent, Loic ^a   Levit, Mikhail N ^b   Windenberger, Fanny ^a   Halley, Frank ^a   Delorme, Ćecile ^a   Lengauer, Christoph ^a   Garcia Echeverria, Carlos ^a   Virone Oddos, Angela ^a  

^a SANOFI   (France)

^b Immunology and Inflammation Development Franchise   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; B RAF KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; SAR 260301; SELUMETINIB; UNCLASSIFIED DRUG; VEMURAFENIB; 2-(2-(2-METHYL-2,3-DIHYDROINDOL-1-YL)-2-OXOETHYL)-6-MORPHOLIN-4-YL-3H-PYRIMIDIN-4-ONE; INDOLE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE 3 KINASE; PROTEIN BINDING; PROTEIN KINASE B; PROTEIN KINASE INHIBITOR; PTEN PROTEIN, HUMAN; PYRIMIDINONE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL LINE; CANCER INHIBITION; CLINICAL ASSESSMENT; CONTROLLED STUDY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; DRUG SELECTIVITY; DRUG TOLERABILITY; ENZYME ACTIVITY; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; IC50; MELANOMA; MELANOMA CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; TUMOR MODEL; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; CONFORMATION; DEFICIENCY; DISEASE MODEL; DRUG EFFECTS; DRUG SCREENING; GENETICS; METABOLISM; MOLECULAR MODEL; MUTATION; ORAL DRUG ADMINISTRATION; PATHOLOGY; TUMOR CELL LINE;

ADMINISTRATION, ORAL; ANIMALS; CELL LINE, TUMOR; CLASS IA PHOSPHATIDYLINOSITOL 3-KINASE; DISEASE MODELS, ANIMAL; DRUG SYNERGISM; FEMALE; HUMANS; INDOLES; MAP KINASE KINASE 1; MAP KINASE SIGNALING SYSTEM; MELANOMA; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MUTATION; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS B-RAF; PROTO-ONCOGENE PROTEINS C-AKT; PTEN PHOSPHOHYDROLASE; PYRIMIDINONES; SIGNAL TRANSDUCTION; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84979248260     PISSN: 15357163     EISSN: 15388514     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-15-0496     Document Type: Article

References (50)

1. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296: 1655-7.
2. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7: 606-19.
3. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/ AKT pathway. Proc Natl Acad Sci U S A 1999;96:4240-5.
4. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
5. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008;27:5486-96.
6. Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, et al. Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci Signal 2008;1:ra3.
7. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, et al. Essential roles of PI(3)Kp110beta in cell growth, metabolism and tumorigenesis. Nature 2008;454:776-9.
8. Wee S, Wiederschain D, Maira SM, Loo A, Miller C, deBeaumont R, et al. PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A 2008;105:13057-62.
9. Certal V, Carry JC, Halley F, Virone-Oddos A, Thompson F, Filoche-Romme B, et al. Discovery and optimization of pyrimidone indoline amide PI3Kbeta inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers. J Med Chem 2014;57: 903-20.
10. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7:295-308.
11. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-54.
12. Sullivan RJ, Flaherty K. MAP kinase signaling and inhibition in melanoma. Oncogene 2013;32:2373-9.
13. Davies MA. The role of the PI3K-AKT pathway in melanoma. Cancer J 2012;18:142-7.
14. Kwong LN, Davies MA. Navigating the therapeutic complexity of PI3K pathway inhibition in melanoma. Clin Cancer Res 2013;19: 5310-9.
15. Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res 2011;71:2750-60.
16. Xing F, Persaud Y, Pratilas CA, Taylor BS, Janakiraman M, She QB, et al. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene 2012; 31:446-57.
17. Nathanson KL, Martin AM, Wubbenhorst B, Greshock J, Letrero R, D'Andrea K, et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res 2013;19:4868-78.
18. Ratkowsky DA, Reedy TJ. Choosing near-linear parameters in the fourparameter logistic model for radioligand and related assays. Biometrics 1986;42:575-82.
19. Fabian MA, Biggs WHIII, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005;23:329-36.
20. Patricelli MP, Nomanbhoy TK, Wu J, Brown H, Zhou D, Zhang J, et al. In situ kinase profiling reveals functionally relevant properties of native kinases. Chem Biol 2011;18:699-710.
21. Ronan B, Flamand O, Vescovi L, Dureuil C, Durand L, Fassy F, et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol 2014;10:1013-9.
22. Certal V, Halley F, Virone-Oddos A, Thompson F, Filoche-Romme B, El Ahmad Y, et al. Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kbeta inhibitors. Bioorg Med Chem Lett 2012;22:6381-4.
23. Certal V, Halley F, Virone-Oddos A, Delorme C, Karlsson A, Rak A, et al. Discovery and optimization of new benzimidazole- and benzoxazolepyrimidone selective PI3Kbeta inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. J Med Chem 2012;55:4788-805.
24. Straetemans R, O'Brien T, Wouters L, Van Dun J, Janicot M, Bijnens L, et al. Design and analysis of drug combination experiments. Biom J 2005;47: 299-308.
25. Copeland RA. Enzymes: a practical introduction to structure, mechanism, and data analysis. 2nd ed. New York, NY: Wiley-VCH; 2000.
26. Byron SA, Loch DC, Wellens CL, Wortmann A, Wu J, Wang J, et al. Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status. Mol Cancer 2012;11:75.
27. Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, et al. Functional characterization of an isoform-selective inhibitor of PI3K-p110beta as a potential anticancer agent. Cancer Discov 2012;2:425-33.
28. Hancox U, Cosulich S, Hanson L, Trigwell C, Lenaghan C, Ellston R, et al. Inhibition of PI3Kbeta signaling with AZD8186 inhibits growth of PTENdeficient breast and prostate tumors alone and in combination with docetaxel. Mol Cancer Ther 2015;14:48-58.
29. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 2013;10:143-53.
30. Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, Liu M, et al. Characterization of the novel and specific PI3Kalpha inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther 2014;13:1117-29.
31. Marques RB, Aghai A, de Ridder CM, Stuurman D, Hoeben S, Boer A, et al. High efficacy of combination therapy using PI3K/AKT inhibitors with androgen deprivation in prostate cancer preclinical models. Eur Urol 2015;67:1177-85.
32. Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V, et al. Feedback suppression of PI3Kalpha signaling in PTENmutated tumors is relieved by selective inhibition of PI3Kbeta. Cancer Cell 2015;27:109-22.
33. Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, Jakubik CT, et al. Measurement of PIP3 levels reveals an unexpected role for p110beta in early adaptive responses to p110alpha-specificinhibitorsinluminal breast cancer. Cancer Cell 2015;27:97-108.
34. Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 1997;57:5221-5.
35. Tsao H, Zhang X, Benoit E, Haluska FG. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 1998;16:3397-402.
36. Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene 2003;22:3113-22.
37. Bucheit AD, Chen G, Siroy A, Tetzlaff M, Broaddus R, Milton D, et al. Complete loss of PTEN protein expression correlates with shorter time to brain metastasis and survival in stage IIIB/C melanoma patients with BRAFV600 mutations. Clin Cancer Res 2014;20:5527-36.
38. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WEJr, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 2009;41:544-52.
39. Bedogni B, Welford SM, Kwan AC, Ranger-Moore J, Saboda K, Powell MB. Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model. Mol Cancer Ther 2006;5:3071-7.
40. Meier F, Busch S, Lasithiotakis K, Kulms D, Garbe C, Maczey E, et al. Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment. Br J Dermatol 2007;156:1204-13.
41. Aziz SA, Jilaveanu LB, Zito C, Camp RL, Rimm DL, Conrad P, et al. Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma. Clin Cancer Res 2010;16:6029-39.
42. Gopal YN, Deng W, Woodman SE, Komurov K, Ram P, Smith PD, et al. Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res 2010;70:8736-47.
43. Deng W, Gopal YN, Scott A, Chen G, Woodman SE, Davies MA. Role and therapeutic potential of PI3K-mTOR signaling in denovo resistance to BRAF inhibition. Pigment Cell Melanoma Res 2012;25:248-58.
44. Ho AL, Musi E, Ambrosini G, Nair JS, Deraje VS, De Stanchina E, et al. Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype. PLoS One 2012;7:e40439.
45. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 2010;18:683-95.
46. Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, et al. Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS One 2011;6:e28973.
47. Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther 2012;11:909-20.
48. Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, et al. Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res 2009;15:7538-46.
49. Blackman SC, Gainer SD, Suttle BB, Skordos KW, Greshock JD, Motwani M, et al. A phase I/IIa, first time in human, open-label dose-escalation study of GSK2636771 in subjects with advanced solid tumors with PTEN deficiency [abstract]. In:Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; 2012. Abstract nr 1752.
50. Barry ST, Cronin K, Cumberbatch M, Ellston R, Foster E, Hancox U, et al. The Pi3Kβ/d inhibitor AZD8186 has potential to treat tumours in combination with key signalling pathway inhibitors [abstract]. In:Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; 2014. Abstract nr 4249.