The present and future of PI3K inhibitors for cancer therapy

被引：122

作者：

Castel, Pau ^{[1
]}

Toska, Eneda ^{[2
,3
]}

Engelman, Jeffrey A. ^{[4
]}

Scaltriti, Maurizio ^{[5
]}

机构：

[1] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[2] Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Canc Ctr, Baltimore, MD 21205 USA

[3] Johns Hopkins Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD USA

[4] Treeline Biosci, Watertown, MA USA

[5] AstraZeneca, Early Oncol, Waltham, MA 02154 USA

来源：

NATURE CANCER | 2021年 / 2卷 / 06期

关键词：

PHOSPHATIDYLINOSITOL 3-KINASE INHIBITION; BUPARLISIB PLUS TRASTUZUMAB; METASTATIC BREAST-CANCER; GROWTH-FACTOR RECEPTOR; IMPAIRED B-CELL; PHASE-I; DOSE-ESCALATION; DOUBLE-BLIND; PI3K-ALPHA INHIBITION; HIGH-FREQUENCY;

D O I：

10.1038/s43018-021-00218-4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Phosphoinositide 3-kinase (PI3K) signaling regulates cellular proliferation, survival and metabolism, and its aberrant activation is one of the most frequent oncogenic events across human cancers. In the last few decades, research has focused on the development of PI3K inhibitors, from preclinical tool compounds to the highly specific medicines approved to treat patients with cancer. Herein we discuss current paradigms for PI3K inhibitors in cancer therapy, focusing on clinical data and mechanisms of action. We also discuss current limitations in the use of PI3K inhibitors, including toxicities and mechanisms of resistance, with specific emphasis on approaches aimed at improving efficacy. Scatiltri and colleagues review the paradigms of targeting PI3K in solid tumors in the clinic, including the progress so far in developing effective inhibitors as well as clinical limitations due to toxicity and therapeutic resistance.

引用

页码：587 / 597

页数：11

共 125 条

[1] Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer [J].

Ali, Khaled ;

Soond, Dalya R. ;

Pineiro, Roberto ;

Hagemann, Thorsten ;

Pearce, Wayne ;

Lim, Ee Lyn ;

Bouabe, Hicham ;

Scudamore, Cheryl L. ;

Hancox, Timothy ;

Maecker, Heather ;

Friedman, Lori ;

Turner, Martin ;

Okkenhaug, Klaus ;

Vanhaesebroeck, Bart .

NATURE, 2014, 510 (7505) :407-+

[2] Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer [J].

Andre, Fabrice ;

Ciruelos, Eva ;

Rubovszky, Gabor ;

Campone, Mario ;

Loibl, Sibylle ;

Rugo, Hope S. ;

Iwata, Hiroji ;

Conte, Pierfranco ;

Mayer, Ingrid A. ;

Kaufman, Bella ;

Yamashita, Toshinari ;

Lu, Yen-Shen ;

Inoue, Kenichi ;

Takahashi, Masato ;

Papai, Zsuzsanna ;

Longin, Anne-Sophie ;

Mills, David ;

Wilke, Celine ;

Hirawat, Samit ;

Juric, Dejan .

NEW ENGLAND JOURNAL OF MEDICINE, 2019, 380 (20) :1929-1940

[3] Two signaling pathways can lead to Fas ligand expression in CD8(+) cytotoxic T lymphocyte clones [J].

Anel, A ;

Simon, AK ;

Auphan, N ;

Buferne, M ;

Boyer, C ;

Golstein, P ;

SchmittVerhulst, AM .

EUROPEAN JOURNAL OF IMMUNOLOGY, 1995, 25 (12) :3381-3387

[4] Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage [J].

Angulo, Ivan ;

Vadas, Oscar ;

Garcon, Fabien ;

Banham-Hall, Edward ;

Plagnol, Vincent ;

Leahy, Timothy R. ;

Baxendale, Helen ;

Coulter, Tanya ;

Curtis, James ;

Wu, Changxin ;

Blake-Palmer, Katherine ;

Perisic, Olga ;

Smyth, Deborah ;

Maes, Mailis ;

Fiddler, Christine ;

Juss, Jatinder ;

Cilliers, Deirdre ;

Markelj, Gasper ;

Chandra, Anita ;

Farmer, George ;

Kielkowska, Anna ;

Clark, Jonathan ;

Kracker, Sven ;

Debre, Marianne ;

Picard, Capucine ;

Pellier, Isabelle ;

Jabado, Nada ;

Morris, James A. ;

Barcenas-Morales, Gabriela ;

Fischer, Alain ;

Stephens, Len ;

Hawkins, Phillip ;

Barrett, Jeffrey C. ;

Abinun, Mario ;

Clatworthy, Menna ;

Durandy, Anne ;

Doffinger, Rainer ;

Chilvers, Edwin R. ;

Cant, Andrew J. ;

Kumararatne, Dinakantha ;

Okkenhaug, Klaus ;

Williams, Roger L. ;

Condliffe, Alison ;

Nejentsev, Sergey .

SCIENCE, 2013, 342 (6160) :866-871

[5] The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumourgrowth [J].

Bago, Ruzica ;

Sommer, Eeva ;

Castel, Pau ;

Crafter, Claire ;

Bailey, Fiona P. ;

Shpiro, Natalia ;

Baselga, Jose ;

Cross, Darren ;

Eyers, Patrick A. ;

Alessi, Dario R. .

EMBO JOURNAL, 2016, 35 (17) :1902-1922

[6]

Bailey MH, 2018, CELL, V173, P371, DOI [10.1016/j.cell.2018.02.060, 10.1016/j.cell.2018.07.034]

[7] Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial [J].

Baselga, Jose ;

Im, Seock-Ah ;

Iwata, Hiroji ;

Cortes, Javier ;

De laurentiis, Michele ;

Jiang, Zefei ;

Arteaga, Carlos L. ;

Jonat, Walter ;

Clemons, Mark ;

Ito, Yoshinori ;

Awada, Ahmad ;

Chia, Stephen ;

Jagiello-Gruszfeld, Agnieszka ;

Pistilli, Barbara ;

Tseng, Ling-Ming ;

Hurvitz, Sara ;

Masuda, Norikazu ;

Takahashi, Masato ;

Vuylsteke, Peter ;

Hachemi, Soulef ;

Dharan, Bharani ;

Di Tomaso, Emmanuelle ;

Urban, Patrick ;

Massacesi, Cristian ;

Campone, Mario .

LANCET ONCOLOGY, 2017, 18 (07) :904-916

[8] Phase I, Dose-Escalation Study of BKM120, an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors [J].

Bendell, Johanna C. ;

Rodon, Jordi ;

Burris, Howard A. ;

de Jonge, Maja ;

Verweij, Jaap ;

Birle, Diana ;

Demanse, David ;

De Buck, Stefan S. ;

Ru, Qinhua C. ;

Peters, Malte ;

Goldbrunner, Michael ;

Baselga, Jose .

JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (03) :282-290

[9] PI3K isoforms in cell signalling and vesicle trafficking [J].

Bilanges, Benoit ;

Posor, York ;

Vanhaesebroeck, Bart .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2019, 20 (09) :515-534

[10] PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer [J].

Bosch, Ana ;

Li, Zhiqiang ;

Bergamaschi, Anna ;

Ellis, Haley ;

Toska, Eneda ;

Prat, Aleix ;

Tao, Jessica J. ;

Spratt, Daniel E. ;

Viola-Villegas, Nerissa T. ;

Castel, Pau ;

Minuesa, Gerard ;

Morse, Natasha ;

Rodon, Jordi ;

Ibrahim, Yasir ;

Cortes, Javier ;

Perez-Garcia, Jose ;

Galvan, Patricia ;

Grueso, Judit ;

Guzman, Marta ;

Katzenellenbogen, John A. ;

Kharas, Michael ;

Lewis, Jason S. ;

Dickler, Maura ;

Serra, Violeta ;

Rosen, Neal ;

Chandarlapaty, Sarat ;

Scaltriti, Maurizio ;

Baselga, Jose .

SCIENCE TRANSLATIONAL MEDICINE, 2015, 7 (283)

← 1 2 3 4 5 6 7 8 9 10 →