molecular pathways: targeting phosphoinositide 3-kinase...

Molecular Pathways

Molecular Pathways: Targeting Phosphoinositide 3-Kinasep110-Delta in Chronic Lymphocytic Leukemia

Sarah E.M. Herman1 and Amy J. Johnson2,3

AbstractThe advent of targeted therapy, specifically to the B-cell receptor (BCR), has changed the convention for

the treatment of chronic lymphocytic leukemia (CLL). The phosphoinositide 3-kinase (PI3K) pathway,

activated upstream by the BCR, receptor tyrosine kinases, and cytokine receptors, has been a potential target

for a multitude of cancers, but until the recent introduction of isoform-specific inhibitors has not been

widely used. In this review,we focus ondescribing the intricate upstreamanddownstream signaling, leading

to cell survival mediated by PI3K in B cells with a specific focus on the impact and importance of the p110disoform (which is localized to hematopoietic cells and regulates distinct cellular functions in B cells). In

addition, the clinical advances from targeting p110d are described, with a focus on clinical outcome,

toxicities, and rational combination therapies. The experiences with p110d in CLL have led to a more

fundamental understanding of CLL signaling defects and may be predictive of other BCR-directed

therapeutics. Clin Cancer Res; 18(15); 4013–8. �2012 AACR.

BackgroundThe phosphoinositide 3-kinase pathway in chroniclymphocytic leukemiaCellular signaling involving protein kinases regulates

important cellular functions including proliferation,growth, and cell survival; one such pathway is the phos-phoinositide 3-kinase (PI3K) pathway (Fig. 1). There are 3classes of PI3K isoforms; however, only the class I isoformsphosphorylate inositol lipids to form second messengerphosphoinositides and have been associated with tumor-igenesis (1, 2). The class I PI3K isoforms can be subcategor-ized into class IA and class IB PI3Ks (3, 4). Class IAencompasses p110a, p110b, and p110d (catalyticdomains) bound by p85, p50, or p55 (regulatory domains;refs. 3, 5). Class IB is made up solely of the p110g (catalyticdomain) bound by the regulatory domain p101 (3, 5).Activation of PI3K class 1A isoforms can occur via a B-cellreceptor (BCR)-dependent or -independent (via receptortyrosine kinases, cytokine receptors) manner. Upon liga-tion of the BCR, the proteins on the cell surface begin tochange. Although activation is dependent on BCR signalingmediated by the antigen receptor, composed of membrane

immunoglobulin M, it possesses a short cyotoplasmictail incapable of transmitting signals generated by receptorstimulation. Instead, these signals are transduced bythe disulfide-linked helper molecules Iga and Igb that arenoncovalently associated with the antigen receptor. TheIga–Igb complex contains an immunoreceptor tyrosine–based activation motif (ITAM). Upon receptor cross-link-ing, Src family kinases (such as Lyn, Fyn, and Blk) andspleen tyrosine kinase are brought into proximity withthe receptor to phosphorylate the tyrosine residue on theITAM on CD19 and/or BCAP (6–8). This creates an Srchomology 2 (SH2)-binding domain capable of bindingSH2 domain proteins. This occurs similarly with receptortyrosine kinases, where ligand binding leads to autopho-sphorylation of the tyrosine residue on the ITAM, againcreating an SH2-binding domain (9), and with cytokinereceptors, where formation of the receptor complex resultsin activation of the receptor-associated janus-activatedkinase (JAK) tyrosine kinases (10). JAK activation is fol-lowed by phosphorylation of tyrosine residues in variousproteins (including receptors such as gp130 and IRS familymembers) again providing binding sites for SH2 domain–containing proteins (10). The creation of the SH2-bindingdomain allows for the binding of the SH2 domain of thep85 subunit (or another regulatory subunit) of PI3K,allowing for activation of class IA PI3K (11). Once thisoccurs, p85 releases its conformational inhibitory effect onthe catalytic subunit of PI3K (11, 12). Specifically, thecatalytic class I PI3K enzymes are now able to convertPtdIns(3,4)P2 into PtdIns(3,4,5)P3 in the cell membrane(13). These events are directly regulated by 2 phosphates,PTEN and SHIP, both of which hydrolyze PtdIns(3,4,5)P3to PtdIns(4,5)P2 andPtdIns(3,4)P2, respectively (1, 13, 14).

Author's Affiliations: 1Hematology Branch, National Heart, Lung, andBlood Institute, NIH,Bethesda,Maryland; 2DivisionofHematology,Depart-ment of Internal Medicine, and 3Division of Medicinal Chemistry andPharmacognosy, College of Pharmacy, The Ohio State University, Colum-bus, Ohio

Corresponding Author: Amy J. Johnson, The Ohio State Univer-sity, OSU CCC Building, Room 445C, 410 West 12th Avenue, Colum-bus, OH 43210. Phone: 614-292-8265; Fax: 614-292-3312; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-11-1402

�2012 American Association for Cancer Research.

ClinicalCancer

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© 2012 American Association for Cancer Research

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AKT

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Herman and Johnson

Clin Cancer Res; 18(15) August 1, 2012 Clinical Cancer Research4014




In addition to class IA PI3Ks, there also exists class IB PI3Ksthat function identically but are activated by G-protein–coupled receptors and regulated by a p101 subunit (3, 5).Regardless, once PtdIns(3,4)P2 has been phosphorylated toPtdIns(3,4,5)P3, it recruits via binding to the amino-termi-nal pleckstrin homology (PH) domain and downstreamsignaling proteins such as Tec kinases, PDK (phosphoinosi-tide-dependent kinases), Akt, ILK, and Rac GEF. The pro-totype of thesemolecules is Akt (also known as PKB), whichfunctions as 3 serine/threoninekinases (Akt1/2/3) that havea broad range of substrates (15). The role of the PI3K/AKTpathway in cell survival has been well described, with thePI3K/AKT pathway acting to antagonize apoptosis, promot-ed by a variety of environmental stresses, through interfer-ing with downstream proteins (15–17). Binding of PI3K toPDK leads to phosphorylation of Akt at threonine-308 andserine-473 (15, 17). This activation of Akt leads to increasedsurvival in a dual fashion: first, by inhibiting activation ofapoptosis (by interfering with the expression of FasL, sup-pression of the extrinsic caspase cascade by inhibition ofdeath gene transcription, and repression of the intrinsiccaspase cascade by decreasing the dissociation of the Bad/Bcl-XL complex, inhibition of cytochrome c release, andphosphorylation and thus inactivation of caspase 9) andalso by activating NF-kB (which turns on cell survivalsignals such as c-FLIP that block caspase-8 activation;refs. 16–18). Thus, activation of the PI3K/AKT pathwayincreases activation of survival signals, whereas concurrent-ly inhibiting apoptotic signals leads to an overall increase incell survival.

Validation of p110d as a therapeutic target for chroniclymphocytic leukemiaWith the PI3K/AKT pathway playing such a diverse role in

the regulation of cell survival/apoptosis, it is a prime targetfor the treatment of B-cell malignancies such as chroniclymphocytic leukemia (CLL), characterized by prolongedmalignant cell survival. However, inhibiting the PI3K/AKTpathway has proved quite complex, as the pathway isinvolved in the maintenance of a multitude of cell typesand it is critical to fundamental cell processes such asmetabolism, growth, proliferation, and survival (1, 17). Itis thought that this widespread functionality of PI3K signal-ing is at least partially responsible for the significant toxicityassociated with pan-PI3K inhibitors, as these inhibitors(such as LY294002 and wortmannin) typically inhibit all

of the class I PI3K isoforms (14, 19). The most notable ofthese is the induction of hyperglycemia caused by inhibitionofPI3K (specifically p110a) in theb islet cells of thepancreas(14). In recent years, it has been shown that the differentclass I isoforms have nonredundant roles and differentexpression profiles in different cell types (3, 20–22). Thep110a and p110b isoforms are ubiquitously expressed, andknockoutmice for both are embryonic lethal (4). In the pastdecade, it has been determined that the p110d and p110gisoforms of PI3K are expressed primarily in cells of hemato-poietic lineage, suchasBandT cells (12,23). This suggests animportant role for these isoforms of PI3K in B cells. Fur-thermore, mice with deleted or mutated p110d exhibit aB-cell defect with a lack of B1 lymphocytes (as well asmarginal zone B cells), decreased mature B cell numbers,and impaired antibody production (4, 20, 24). Biochemi-cally, B cells derived from p110d knockout mice also showless AKT phosphorylation when activated and havedecreased PtdIns(3,4,5)P3 levels and phosphopeptide activ-ity (4). In contrast, p110g isoformknockoutmice, while notembryonic lethal, have predominantly a T-cell defect withno B-cell developmental or functional abnormalities (4).These mouse studies suggest that isoform-specific targetingof the p110d isoform may be cytotoxic to B cells withminimal toxicity to other hematopoietic cell types. To fur-ther understand the role of p110d in B cells, forced expres-sionofp110dwasevaluatedand found tobe transforming incell lines (25). InCLL cells, PI3K signaling has been found tobe constitutively activated and at least in IGHV, unmutatedCLL has been found to be overexpressed at the gene level(26).Moreover, in vitro studieshave shown increased generalactivity of PI3K in the pathogenesis of CLL and other B-celldiseases with convergence of CD40L, BAFF, fibronectin, andBCR signaling through this pathway (27–31). The specificityof the p110d makes it a promising drug target for B-celllymphoproliferative disorders, including CLL, as it reducesthe cellular toxicity associated with nonspecific PI3K inhi-bitors by reducing the off-target effects in nonhematopoietictissues, while maintaining the ability to inhibit the PI3Kpathway in a way that alters B-cell survival.

Clinical–Translational AdvancesGS-1101 (CAL-101)—a selective p110d inhibitor

The identification of the hematopoietic-selective isoformp110d unlocks a new therapeutic potential for B-cell malig-nancies as it led to the clinical development of isoform-

Figure 1. PI3K signaling can be activated via a variety of methods, including stimulation from the microenvironment leading to engagement of the BCR,cytokine receptors, or receptor tyrosine kinases (RTK).Upon receptor activation, accessorymolecules lead to the activation ofPI3K. All the3class 1A isoformsof PI3K (p110a, p110b, and p110d) facilitate the phosphorylation of phosphatidylinositol (3,4)-biphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3), leading to the phosphorylation of downstream signaling molecules. GS-1101, a selective p110d isoform inhibitor, thereby prevents theactivity of PI3K and thus inhibits the phosphorylation of downstream kinases, the hallmark of which is AKT. By preventing the phosphorylation of AKT, GS-1101 alters cell homeostasis by (i) preventing the phosphorylation of GSK3b and thereby preventing the transcription of survival genes induced by intactb-catenin; (ii) preventing the phosphorylation of caspase 9, leaving its protease activity intact and allowing for activation of the intrinsic caspase cascade;(iii) preventing the phosphorylation of Frhl1, which blocks the binding of 14-3-3, allowing Frkh1 to translocate to the nucleus and transcribe genesrelated to cell death (such as FasL); and (iv) preventing the phosphorylation of the IKK complex, which inhibits its ability to phosphorylate IKBa, preventing thereleaseof theNF-kBcomplex and translocation to thenucleus, thereby again preventing survival gene transcription. Thus, inhibition of p110d byGS-1101 tipsthe signaling balance from cell survival to cell death.

PI3-Kinase p110-Delta in CLL

www.aacrjournals.org Clin Cancer Res; 18(15) August 1, 2012 4015




specific kinase inhibitors. One such agent is GS-1101 (for-mally known as CAL-101), the first p110d inhibitor inclinical use, initially developed by Calistoga Pharmaceuti-cals and now Gilead. GS-1101 is an orally bioavailable,potent, and selective inhibitor of the p110d isoform that iscurrently under clinical evaluation in B-cell malignancies(32, 33). In vitro, the selectivity of GS-1101 to p110d hasbeen reported to be IC50 of 2.5 nmol/L compared with 820,565, and 89 nmol/L for p110a, b, and g , respectively (34).In addition, GS-1101 was found to be 400-fold moreselective for class I PI3K than other related kinases (34).GS-1101 is thus a selective p110d inhibitor that has thepotential to be a relevant therapeutic for CLL and otherrelated disorders.

Preclinical antitumor activity of GS-1011GS-1101 has been shown to affect cell survival and

microenvironmental signaling in vitro and in vivo. In vitro,we have shown that patients with CLL express p110d(at both the gene and protein level), the target for GS-1101 (35). Subsequently, we found that GS-1101 caninduce apoptosis in CLL cells, although responses varied.Lannutti and colleagues further showed an observed sig-nificant sensitivity (defined as an EC50 < 1 mmol/L) toCAL-101 in 26% of the CLL samples (11 of 42) evaluated(34). We found that the induction of apoptosis was selec-tive for CLL cells as compared with normal B cells or otherhematopoietic cells and occurred independently of tradi-tional prognostic markers (such as cytogenetic abnormalityor IGVH mutational status; ref. 35). Furthermore, theinduction of apoptosis via GS-1101 was found to be viaa caspase-dependent mechanism (35). In addition to adirect induction of apoptosis, we showed that GS-1101 caninhibit induced survival mechanisms by blocking the pro-tective effect of multiple microenvironmental stimuli (suchas CD40L) by preventing activation of downstream signal-ing (such as phosphorylation of AKT; ref. 35). Similarly,Fiorcari and colleagues recently presented data suggestingthat GS-1101 can overcome both BMSC- and EC-mediatedCLL cell protection, indicating that GS-1101 inhibitsBMSC- and EC-derived prosurvival signals (36). Morerecently, Hoellenriegel and colleagues showed that GS-1101 can inhibit both the chemotaxis toward CXCL12and CXCL13 and the migration beneath stroma cell layers,suggesting a potential mobilization effect (37). In addition,they showed that GS-1101 inhibits chemokine (such asCCL3 and CCL4) and cytokine (such as interleukin-6 andTNF) secretion mediated by BCR stimulation or nurse-likecells (37). Concurrent with this, chemosensitization wasobserved to other cytotoxic drugs (such as fludarabineand bendamustine; ref. 37). Along these lines, Davids andcolleagues recently presented data suggesting that GS-1101can sensitize stroma-exposed CLL cells to other agents (suchas fludarabine) by inhibition of stroma–CLL contact, lead-ing to an increase in mitochondrial apoptotic priming ofthe CLL cells (38). These data suggest that GS-1101 will bebeneficial in the treatment of CLL by acting to directlyinduce apoptosis and to inhibit microenvironmental inter-

actions, which would be leading to increased cellular sur-vival, proliferation, and migration.

Clinical experience with GS-1101Clinical results from either the single-agent CAL-101

(GS-1101) trial or dual therapy trials involving GS-1101have not yet been published in manuscript form and todate have only been presented in part at internationalmeetings; however, even early clinical trial data suggestpromising results. At the American Society of Hematology(ASH) 2010 scientific meeting, Furman and colleaguesreported the results from the first 37 patients treated withGS-1101. These patients showed a significant decrease inlymphadenopathy (occurring in 100% of the patientswith bulky disease) with 91% of patients having at leasta 50% reduction in lymph node size (39). As expected,significant lymphocytosis [absolute lymphocyte count(ALC) rising by more than 50% compared with baseline]occurred in 60% of patients with maxima during the first2 cycles of treatment (39). Despite the lymphocytosis,when traditional response criteria were applied the overallprogressive response rate was 33% (39). Pharmacody-namic studies on peripheral blood mononuclear cellsshowed a decrease in phosphorylated AKT after just1 week of treatment (39). Corroborating these results,Hoellenriegel and colleagues showed that patients withCLL receiving GS-1101 showed decreases in CLL3, CLL4,and CXCL13 as well as reduced phosphorylation of AKT(threonine-308) by the end of the first cycle (37). Coutreand colleagues updated the patient responses in mid-2011 with a total of 54 patients enrolled. The ALC trendsstill uphold leaving the overall intention-to-treat responserate by International Workshop on Chronic LymphocyticLeukemia 2008 criteria at 26%; despite this, however,46% of patients remained on treatment (32). In additionto GS-1101 as a single agent, it is currently being inves-tigated in combination with rituximab, bendamustine,ofatumumab, and fludarabine. The first reports of GS-1101 in combination therapy in CLL were presentedbriefly at the ASH 2010 meeting followed by an updateat the ASCO meeting in 2011. In 2011, Flinn and col-leagues reported that compared with baseline, on-treat-ment peripheral lymphocyte counts were stable ordecreased in 8 of 8 patients with CLL (40). Followingup on this study, Sharman and colleagues reported thatalthough lymphocyte mobilization occurred in somepatients, it was not as prominent as what had beenreported for the single-agent studies (33). A distinctreduction in lymphadenopathy (>50% decrease in lymphnode area) was observed in more than 75% of patients(33). Furthermore, Sharman and colleagues reported thatthe GS-1101 combination trial with rituximab and bend-amustine showed a 80% clinical response rate concurrentwith a decrease in CLL-associated chemokines and cyto-kines such as CCL3, CLL4, CXCL13, and TNF-a (33).Together, this suggests that although GS-1101 is showingpromising results as a single agent, it is showing evengreater potential in combination studies.

Herman and Johnson





ConclusionsInhibition of p110d signaling in CLL appears to be a

promising new therapeutic approach in treating CLL.Although GS-1101 is the only well-described p110dmolecule for the treatment of lymphoid malignancies,multiple other compounds are currently entering clin-ical development, further showing the legitimacy ofp110d as a target. Although preliminary clinical trialdata have shown promising results, combination stud-ies (such as those currently under way with anti-CD20antibodies and bendamustine) are of even greater inter-est, given the distinct differences in the mechanismsof action of such kinase inhibitors and traditionalchemotherapeutics or antibody therapy and the prom-ising preliminary results currently available. Ongoingstudies to discover the influence of PI3K in the micro-environment are important and will help our under-standing of the differential effects on cells in the peri-

phery and lymph node niches and the ongoinglymphocytosis.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interests were disclosed.

Authors' ContributionsConception and design: A.J. Johnson, S.E.M. HermanDevelopment of methodology: S.E.M. HermanWriting, review, and/or revision of the manuscript: A.J. Johnson, S.E.M.HermanAdministrative, technical, or material support (i.e., reporting or orga-nizing data, constructing databases): S.E.M. Herman

Grant SupportThis work was supported by The Leukemia and Lymphoma Society and

the National Cancer Institute (P50 CA140158, PO1 CA95426, PO1CA81534, 1K12 CA133250). Mr. and Mrs. Michael Thomas, The HarryMangurian Foundation, and The D. Warren Brown Foundation also sup-ported this work.

Received March 9, 2012; accepted June 9, 2012; published OnlineFirstJune 18, 2012.

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Herman and Johnson





2012;18:4013-4018. Published OnlineFirst June 18, 2012.Clin Cancer Res Sarah E.M. Herman and Amy J. Johnson p110-Delta in Chronic Lymphocytic LeukemiaMolecular Pathways: Targeting Phosphoinositide 3-Kinase

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