Phosphoproteomics Identifies PI3K Inhibitor-selective Adaptive Responses in Pancreatic Cancer Cell Therapy and Resistance.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
23
11
2020
revised:
28
05
2021
accepted:
14
09
2021
pubmed:
24
9
2021
medline:
26
3
2022
entrez:
23
9
2021
Statut:
ppublish
Résumé
The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform-selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform selectivity toward PI3Kα, PI3Kβ, or PI3Kγ (namely, A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced reactivation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved α-selective BYL-719 with γ-selective IPI-549 was more efficient than single-molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.
Identifiants
pubmed: 34552006
pii: 1535-7163.MCT-20-0981
doi: 10.1158/1535-7163.MCT-20-0981
doi:
Substances chimiques
Phosphoinositide-3 Kinase Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2433-2445Informations de copyright
©2021 American Association for Cancer Research.
Références
Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11:329–41.
Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505:495–501.
Pons-Tostivint E, Thibault B, Guillermet-Guibert J. Targeting PI3K signaling in combination cancer therapy. Trends Cancer. 2017;3:454–69.
Al-Qassab H, Smith MA, Irvine EE, Guillermet-Guibert J, Claret M, Choudhury AI, et al. Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab. 2009;10:343–54.
Martin V, Guillermet-Guibert J, Chicanne G, Cabou C, Jandrot-Perrus M, Plantavid M, et al. Deletion of the p110beta isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo. Blood. 2010;115:2008–13.
Graupera M, Guillermet-Guibert J, Foukas LC, Phng L-K, Cain RJ, Salpekar A, et al. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature. 2008;453:662–6.
Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, et al. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci U S A. 2008;105:8292–7.
André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA -mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929–40.
Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009;16:21–32.
Castellano E, Downward J. RAS interaction with PI3K: more than just another effector pathway. Genes Cancer. 2011;2:261–74.
Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, Jakubik CT, et al. Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. Cancer Cell. 2015;27:97–108.
Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V, et al. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell. 2015;27:109–22.
Zecchin D, Moore C, Michailidis F, Horswell S, Rana S, Howell M, et al. Combined targeting of G protein-coupled receptor and EGF receptor signaling overcomes resistance to PI 3K pathway inhibitors in PTEN -null triple negative breast cancer. EMBO Mol Med. 2020;12:e11987.
Schlieman MG, Fahy BN, Ramsamooj R, Beckett L, Bold RJ. Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br J Cancer. 2003;89:2110–5.
Kong B, Wu W, Cheng T, Schlitter AM, Qian C, Bruns P, et al. A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling. Gut. 2016;65:647–57.
Baer R, Cintas C, Dufresne M, Cassant-Sourdy S, Schönhuber N, Planque L, et al. Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α. Genes Dev. 2014;28:2621–35.
Wu C-YC, Carpenter ES, Takeuchi KK, Halbrook CJ, Peverley LV, Bien H, et al. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology. 2014;147:1405–16.
Hobbs GA, Baker NM, Miermont AM, Thurman RD, Pierobon M, Tran TH, et al. Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discov. 2020;10:104–23.
Cayron C, Guillermet-Guibert J. The type of KRAS mutation drives PI3Kα/γ signalling dependency: implication for the choice of targeted therapy in pancreatic adenocarcinoma patients. Clin Res Hepatol Gastroenterol. 2021;45:101473.
Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B, et al. Binding of Ras to phosphoinositide 3-kinase p110α is required for Ras-driven tumorigenesis in mice. Cell. 2007;129:957–68.
Mueller S, Engleitner T, Maresch R, Zukowska M, Lange S, Kaltenbacher T, et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature. 2018;554:62–8.
Cintas C, Douche T, Therville N, Arcucci S, Ramos-Delgado F, Basset C, et al. Signal-targeted therapies and resistance mechanisms in pancreatic cancer: future developments reside in proteomics. Cancers. 2018;10:174.
Conway JR, Herrmann D, Evans TJ, Morton JP, Timpson P. Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine. Gut. 2019;68:742–58.
Renz BW, Takahashi R, Tanaka T, Macchini M, Hayakawa Y, Dantes Z, et al. β2 Adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell. 2018;33:75–90.
Kaneda MM, Cappello P, Nguyen AV, Ralainirina N, Hardamon CR, Foubert P, et al. Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression. Cancer Discov. 2016;6:870–85.
Wiśniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nat Methods. 2009;6:359–62.
Larsen MR, Thingholm TE, Jensen ON, Roepstorff P, Jørgensen TJD. Highly selective enrichment of phosphorylated peptides from peptide mixtures using titanium dioxide microcolumns. Mol Cell Proteomics. 2005;4:873–86.
Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, Liu M, et al. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther. 2014;13:1117–29.
Evans CA, Liu T, Lescarbeau A, Nair SJ, Grenier L, Pradeilles JA, et al. Discovery of a selective phosphoinositide-3-kinase (PI3K)-γ inhibitor (IPI-549) as an immuno-oncology clinical candidate. ACS Med Chem Lett. 2016;7:862–7.
Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32:185–203.
Baer R, Cintas C, Therville N, Guillermet-Guibert J. Implication of PI3K/Akt pathway in pancreatic cancer: when PI3K isoforms matter?. Adv Biol Regul. 2015;59:19–35.
Edling CE, Selvaggi F, Buus R, Maffucci T, Di Sebastiano P, Friess H, et al. Key role of phosphoinositide 3-kinase class IB in pancreatic cancer. Clin Cancer Res. 2010;16:4928–37.
Basset C, Guillermet-Guibert J. Attenuating PI3K isoforms in pancreatic cancer: focus on immune PI3Kgamma. Clin Res Hepatol Gastroenterol. 2017;41:351–3.
Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee W-J, et al. A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J. 2011;438:53–62.
Guillermet-Guibert J, Smith LB, Halet G, Whitehead MA, Pearce W, Rebourcet D, et al. Novel role for p110β PI 3-kinase in male fertility through regulation of androgen receptor activity in sertoli cells. PLoS Genet. 2015;11:e1005304.
Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, et al. PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med. 2005;11:507–14.
Chaussade C, Rewcastle GW, Kendall JD, Denny WA, Cho K, Grønning LM, et al. Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling. Biochem J. 2007;404:449–58.
Pomel V, Klicic J, Covini D, Church DD, Shaw JP, Roulin K, et al. Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma. J Med Chem. 2006;49:3857–71.
Geiger T, Wisniewski JR, Cox J, Zanivan S, Kruger M, Ishihama Y, et al. Use of stable isotope labeling by amino acids in cell culture as a spike-in standard in quantitative proteomics. Nat Protoc. 2011;6:147–57.
Shenoy A, Geiger T. Super-SILAC: current trends and future perspectives. Expert Rev Proteomics. 2015;12:13–9.
Soares HP, Al-Toubah TE, Kim RD, Kim J, Lewis NK, Mahipal A. Final report: a phase I trial of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer. J Clin Oncol. 2018;36.
Ng SS, Tsao MS, Nicklee T, Hedley DW. Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res. 2001;7:3269–75.
Diersch S, Wenzel P, Szameitat M, Eser P, Paul MC, Seidler B, et al. Efemp1 and p27(Kip1) modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models. Oncotarget. 2013;4:277–88.
Soares HP, Ming M, Mellon M, Young SH, Han L, Sinnet-Smith J, et al. Dual PI3K/mTOR inhibitors induce rapid overactivation of the MEK/ERK pathway in human pancreatic cancer cells through suppression of mTORC2. Mol Cancer Ther. 2015;14:1014–23.
Zhong H, Sanchez C, Spitzer D, Spitrzer D, Plambeck-Suess S, Gibbs J, et al. Synergistic effects of concurrent blockade of PI3K and MEK pathways in pancreatic cancer preclinical models. PLoS One. 2013;8:e77243.
Alagesan B, Contino G, Guimaraes AR, Corcoran RB, Deshpande V, Wojtkiewicz GR, et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. Clin Cancer Res. 2015;21:396–404.
Guillermet-Guibert J, Saint-Laurent N, Davenne L, Rochaix P, Cuvillier O, Culler MD, et al. Novel synergistic mechanism for sst2 somatostatin and TNFalpha receptors to induce apoptosis: crosstalk between NF-kappaB and JNK pathways. Cell Death Differ. 2007;14:197–208.
Foukas LC, Berenjeno IM, Gray A, Khwaja A, Vanhaesebroeck B. Activity of any class IA PI3K isoform can sustain cell proliferation and survival. Proc Natl Acad Sci U S A. 2010;107:11381–6.
Juric D, Castel P, Griffith M, Griffith OL, Won HH, Ellis H, et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature. 2015;518:240–4.
Cintas C, Guillermet-Guibert J. Heterogeneity of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin activation in cancer: is PI3K isoform specificity important?. Front Oncol. 2017;7:330.
Torres C, Mancinelli G, Cordoba-Chacon J, Viswakarma N, Castellanos K, Grimaldo S, et al. p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity. Proc Natl Acad Sci U S A. 2019;116:14724–33.