CCR FOCUS · Navigating the Therapeutic Complexity of PI3K Pathway Inhibition in Melanoma Lawrence N. Kwong1 and Michael A. Davies2,3 Abstract Melanoma is entering into an era of

Navigating the Therapeutic Complexity of PI3K PathwayInhibition in Melanoma

Lawrence N. Kwong1 and Michael A. Davies2,3

AbstractMelanoma is entering into an era of combinatorial approaches to build upon recent clinical break-

throughs achieved by novel single-agent therapies. One of the leading targets to emerge from the growing

understanding of the molecular pathogenesis, heterogeneity, and resistance mechanisms of melanomas is

the phosphoinositide 3-kinase (PI3K)–AKT pathway. Multiple genetic and epigenetic aberrations that

activate this pathway have been identified in melanomas de novo and in acquired resistance models. These

developments have been paralleled by the establishment of models for preclinical testing and the

availability of compounds that target various effectors in the pathway. Thus, in addition to having a strong

rationale for targeting, the PI3K–AKT pathway presents an immediate clinical opportunity. However, the

development of effective strategies against this pathway must overcome several key challenges, including

optimizing patient selection, overcoming feedback loops, and pathway cross-talk that can mediate

resistance. This review discusses the current understanding and ongoing research about the PI3K–AKT

pathway in melanoma and emerging strategies to achieve clinical benefit in patients by targeting it. Clin

Cancer Res; 19(19); 5310–9. �2013 AACR.

IntroductionThe phosphoinositide 3-kinase (PI3K)–AKT cascade is

one of the most studied pathways in cancer. The pathway isa critical regulator of many essential physiologic processesthat are critical to the aggressive nature and behaviorof malignant cells. Previous studies have shown that thepathway is among the most frequent targets of geneticaberrations across many types of cancer (1). These altera-tions include mutations and copy number changes withinthe core components of the pathway, as well as alterationsin genes that use that pathway as a critical effector [i.e.,receptor tyrosine kinases (RTK)]. For all of these reasons, thePI3K–AKT pathway has also been the focus of aggressivepharmacologic development and testing (2, 3).

The high prevalence of activating mutations in BRAF andNRAS in cutaneous melanomas supports a critical role foractivation of the RAS–RAF–MEK–ERK pathway in the path-ogenesis of this disease (4). However, multiple lines ofevidence have also shown a significant role for the PI3K–AKT pathway. This review highlights some of the key find-ings about the PI3K–AKT pathway in melanoma, and therationale, approaches, and challenges to the developmentof effective therapeutic approaches against it.

Activation of the PI3K–AKT Pathway in MelanomaThe physiologic regulation of the PI3K–AKT cascade is

shown in Fig. 1 (5). PI3K, which consists of a dimer ofcatalytic (i.e., p110) and regulatory (i.e., p85) subunits, canbe activated by multiple signals, including RTKs, RAS pro-teins, and cell–cell contacts, among others. Activated PI3Kphosphorylates phosphatidylinositols in the plasma mem-brane at the 30-OH group. These 30-phospholipids attractproteins that contain a pleckstrin homology domain to thecell membrane, including the serine-threonine kinase AKT.AKT,whichhas three isoforms (AKT1/2/3), is phosphorylatedat two critical and conserved residues, Thr308 (by PDK1) andSer473 (by the mTORC2 complex), which fully activate itscatalytic activity. Activated AKT then phosphorylates a num-ber of effector proteins, thereby regulating multiple keycellular processes, including proliferation, survival, motility,metabolism, angiogenesis, and more. PTEN regulates theactivity of the pathway by dephosphorylating phosphatidy-linositols at the 30-position, thereby antagonizing the activityof PI3K (6). Multiple other lipid and protein phosphatasesalso regulate various steps and effectors in the pathway (7).

The PI3K–AKT pathway is activated multiple ways inmelanoma. The two most common and studied events areactivating mutations in the oncogeneNRAS (15–20%) andloss of expression and/or function of the tumor suppressorPTEN (20–30%; ref. 4). Similar to BRAF and NRAS muta-tions in the RAS–RAF–MEK–ERK signaling pathway, NRASmutations and PTENmutations/deletions are largely mutu-ally exclusive. In contrast, PTEN loss commonly occurs inmelanomas with activating BRAF mutations, resulting inconcurrent activation of the RAS–RAF–MEK–ERK andPI3K–AKT pathways (8–10). The generalmutual exclusivity

Authors' Affiliations: Departments of 1Genomic Medicine, 2MelanomaMedical Oncology, and 3Systems Biology, University of Texas MD Ander-son Cancer Center, Houston, Texas

Corresponding Author: Lawrence N. Kwong, The University of Texas MDAnderson Cancer Center, 1515 Holcombe Boulevard, Unit 0091, Houston,TX 77054. Phone: 713-792-6811; Fax: 713-792-6870; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-13-0142

�2013 American Association for Cancer Research.

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ofNRASmutations and PTEN loss in melanoma is thoughtby many to be attributable to the fact that both eventsactivate the PI3K–AKTpathway, thus rendering the presenceof both alterations in the same tumor functionally redun-dant. However, similar to findings in other tumor types,quantitative analysis of melanoma cell lines and clinicalspecimens has shown that melanomas with PTEN lossconsistently have higher levels of AKT activation than thosewith NRAS mutations (11–13). Furthermore, experimentsin a RAS-mutant melanoma genetically engineered mousemodel (GEMM) showed that loss of PTEN increased inva-siveness and metastatic potential (14). Although rare, dele-tions and mutations of PTEN have been detected in somemelanomas with activating NRAS mutations, including intwo recent whole exome sequencing studies of >100 mel-anomas, which also detected PTEN alterations in melano-mas with wild-type BRAF and NRAS (15, 16). However,these data should be interpreted with caution, as no stan-dardized protocol has been established for defining PTEN

deletions. Preliminary analysis of The Cancer GenomeAtlas (TCGA) data suggests that such a standard shouldtake into account both copy number and focality, andwould decrease the discrepancies between studies. Addi-tional studies support that PTEN expression can be regu-lated epigenetically, including by microRNAs and thePTENP1 pseudogene (17–20). A more complete under-standing of the prevalence, pattern, molecular causes, andclinical associations of PTEN losswill likely be possiblewiththe completion of the ongoing melanoma TCGA effort,whichwill includeDNA-, RNA-, and protein-based analysesof up to 500 clinically annotated melanoma specimens.

The functional significance of PTEN loss has been studiedextensively in the setting of melanomas with activatingBRAF mutations. To date, nearly all published patient-derived melanoma cell lines with complete loss of PTENhave concurrent BRAF mutations (11, 21–24). This strongassociation with BRAF mutations has also been shownfunctionally in GEMM. Although expression of the BRAF

© 2013 American Association for Cancer Research

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Figure 1. Regulators, effectors,and somatic alterations inthe PI3K–AKT pathway inmelanoma.

PI3K Pathway Inhibition in Melanoma

www.aacrjournals.org Clin Cancer Res; 19(19) October 1, 2013 5311



V600E protein in murine melanocytes results in increasedproliferation of melanocytes, concurrent PTEN loss resultsin 100% penetrance of invasive, metastatic tumors, thusestablishing the first suchmodel for this disease (25).BRAF-mutant human melanoma cell lines with loss of PTEN aregenerally sensitive to growth inhibition by BRAF and MEKinhibitors, but they are significantly resistant to apoptosisinduction by these treatments (26–29). Supporting theclinical relevance of these findings, two independentanalyses of PTEN status, one genetic and one immuno-histochemical, identified decreased clinical benefit withselective BRAF inhibitors (vemurafenib, dabrafenib) inpatients with loss of PTEN in pretreatment (includingarchival) tumor specimens (30, 31). Although theseresults support the potential value for evaluating PTENfunction in BRAF-mutant melanomas in future studies, itis not yet clear what methodology of PTEN testing (i.e.,DNA-, RNA- or protein-based) will prove most informa-tive. Furthermore, very little information is available atthis time about the concordance of PTEN among differenttumors in individual patients (32).

Both broad and focused sequencing studies have iden-tified additional genetic events that can activate the PI3K–AKT pathway in melanoma. Point mutations in PIK3CA,which encodes the p110a catalytic subunit of PI3K, aredetected in 2% to 6% of melanomas (15, 16, 33, 34).Notably, although some of these mutations are recurrenthotspots reported in other tumor types, others are noveland of unclear functional significance. Mutations produc-ing the activating substitution E17K in AKT1, which aredetected as rare events in several tumor types, have alsobeen detected as rare events in melanoma (1–2%; refs. 35,36). However, melanoma is the only disease in which theanalogous mutation in AKT3 has been detected (1–2%).The identification of AKT3 mutations builds upon previ-ous studies reporting increased expression and activationof AKT3 in melanoma progression, potentially implicat-ing it as a novel therapeutic target (37, 38). Recently,amplification of a 5 Mbp locus including RICTOR, whichencodes a component of the multiprotein TORC2 com-plex that phosphorylates AKT at the Ser473 residue, hasbeen reported in up to 5% of melanomas, particularlythose that are relatively protected from ultraviolet radia-tion (16). Temporally, PI3K activation seems to be asecondary event. In an immunohistochemical survey,PTEN protein loss was observed in melanoma but notin nevi (39), in contrast with the uniformly high muta-tion rate of BRAF across all stages (40). Similarly, phos-phorylated AKT was found to be high in melanoma butnot in nevi (41). The findings are also consistent with lackof the melanocytic phenotype in the PTEN�/� mice in theabsence of the mutant BRAF allele (25).

The PI3K–AKT pathway is also implicated as a criticaleffector of alterations that activate RTKs. Activating muta-tions in c-Kit are rare in cutaneous melanomas, but theyare relatively common in acral and mucosal melanomas(42). Although the low prevalence of BRAF and NRASmutations in these subtypes, and their general mutual

exclusivity with c-Kit mutations, suggested that signalingby mutant KIT proteins might activate the RAS–RAF–MEK–ERK pathway, functional studies in cell lines haveshown activation of, and in some studies dependenceupon, the PI3K–AKT pathway (43–45). One study hasalso reported frequent (�20%) somatic mutations in theERBB4 gene (46). Although these mutations do notcluster in any functional domain, preclinical studies sug-gested that multiple mutant forms of the encoded ERBB4protein activated the PI3K–AKT pathway. However, recentwhole exome-sequencing studies did not identify ERBB4as a significantly mutated gene by the algorithms used inthose analyses (15, 16). In addition to genetic events, itseems that epigenetically mediated activation of RTKsplays a role in melanoma, specifically in resistance toBRAF inhibitors. Two different groups identified increasedexpression and activation of different RTKs [platelet-derivedgrowth factor b (PDGFb) and insulin-like growth factorreceptor (IGF1R), respectively] in progressing tumors andmelanoma cell lines with acquired resistance to BRAF inhi-bitors (47–49). Both groups showed that the activation ofthese RTKs did not rescue the activity of the mitogen-activated protein kinase (MAPK) pathway but insteadcaused compensatory activation of the PI3K–AKT pathway.Importantly, no mutations or amplification in the genesencoding the RTKs were detected in the cell lines. Similarcompensatory activation of this pathway via IGF1Rwas alsoreported in human melanoma cells with de novo resistanceto killing by MEK inhibitors (29). More recently, twodifferent groups showed that secretionof hepatocyte growthfactor by nontransformed cells in the tumor microenviron-ment results in PI3K–AKT pathway activation in melanomacells (50, 51). This interaction caused resistance to BRAFinhibitors in vitro and was correlated with inferior clinicaloutcomes in patients.

PI3K–AKT Pathway InhibitorsThe multiple ways in which the PI3K–AKT pathway is

activated in melanoma, and existing evidence for a func-tional role in progression and resistance, support the ratio-nale to target it therapeutically. Indeed, similar evidencein multiple tumor types has led to the development ofmultiple classes of inhibitors against this pathway. Classesof agents include inhibitors of PI3K (pan-isoform andisoform-specific), dual PI3K–mTOR, AKT, and mTOR(mTORC1 and dual mTORC1/2 inhibitors; Table 1).Multiple agents are available in each class, many of whichare currently undergoing clinical evaluation in patients.Although the availability of this spectrumof agents presentsa tremendous opportunity, a key challenge for a relativelyrare disease such as metastatic melanoma is to rationallyuse and prioritize these agents to determine their clinicalvalue effectively and efficiently.

Experimental evidence from other tumor types supportsthat different ways of activating the PI3K–AKT pathwayresult in functional dependence upon different effectors,and thus sensitivity to different classes of therapeutic agents.

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Clin Cancer Res; 19(19) October 1, 2013 Clinical Cancer Research5312



Melanomas with loss of PTEN represent a high-priorityopportunity, due to the high prevalence of this alterationde novo, the availability ofmodels for functional testing, andthe evidence for a role in resistance to MAPK pathwayinhibitors. Previous studies inmultiple tumor types showedthat loss of PTEN correlates with marked dependence onAKT and sensitivity to AKT inhibition in gene knockdown

experiments (13). However, recently reported experimentsusing the BRAF-mutant, PTEN-null melanoma GEMM sug-gest superior in vivo tumor growth inhibition with PI3Kinhibitors than with AKT inhibitors (52, 53). Althoughthese results are interesting, it remains unclear how wellthis model will reflect results in BRAF-mutant, PTEN-nullmelanomas in patients, which will likely have significant

Table 1. PI3K pathway inhibitors currently in clinical trials for any cancer

Target Inhibitor Alternative name Company

AKT AZD5363 AstraZenecaGDC-0068 GenentechGSK2110183 GlaxoSmithKlineGSK2141795 GlaxoSmithKlineGSK690693 GlaxoSmithKlineKRX-0401 Perifosine KeryxMK2206 MerckSR13668 SRI

mTORC1 Rapamycin Sirolimus PfizerCCI779 Temsirolimus PfizerMK-8669 Ridaforolimus AriadRAD001 Everolimus Novartis

Dual mTORC1/2 AZD2014 AstraZenecaAZD8055 AstraZenecaCC-223 CelgeneMLN0128 INK-128 MilleniumOSI-027 AstellasPalomid 529 Paloma

PI3K p110a-selective GDC-0032 GenentechMLN1117 INK-1117 MilleniumNVP-BYL719 Novartis

PI3K p110b-selective GSK2636771 GlaxoSmithKlineSAR260301 Sanofi-Aventis

PI3K p110d-selective CAL101 GileadGSK2269557 GlaxoSmithKline

Pan PI3K BAY80-6946 BayerGDC-0941 GenentechNVP-BKM120 NovartisPX866 OncothyreonSF1126 SemaforeXL147 SAR245408 ExelixisZSTK474 Zenyaku Kogyo

Dual PI3K/mTOR DS-7423 Daiichi SankyoGDC-0980 GenentechGSK2126458 GlaxoSmithKlineNVP-BEZ235 NovartisNVP-BGT226 NovartisP7170 PiramalPF-05212384 PfizerPF-4691502 PfizerXL765 SAR245409 Exelixis





heterogeneity and additional molecular alterations thatcannot be modeled easily in GEMM systems. Testing ofdual PI3K–mTOR inhibitors in melanoma cell lines hasshown that these agents are broadly inhibitory, and oftensuperior to the inhibition achieved by PI3K or mTORinhibition alone (54, 55). Although improved antitumoractivity is preferred, a key question is whether this willtranslate into an acceptable therapeutic index in patientsdue to the broad physiologic functions of PI3K andmTOR. Recently reported experiments in other modelshave suggested that the efficacy of AKT inhibitors isrelatively selective for tumors with PTEN loss (56). It ispossible that this selectivity for cells with loss of PTENwilltranslate into selective killing of tumor cells in patientswith AKT inhibitors at clinically tolerated doses, even ifthey are less potent. Rapamycin and its analogues, whichinhibit mTORC1, are reasonably well tolerated clinically,as shown by long-standing use in patients who haveundergone organ transplantation. However, mTORC1inhibitors have not shown significant clinical activity assingle agents in metastatic melanoma patients, or incombination with RAF inhibitors (57–59). As discussedbelow, this lack of activity may be due to compensatoryhyperactivation of AKT due to inhibition of an mTORC1-mediated negative feedback loop within the PI3K path-way. In contrast, dual mTORC1/2 inhibitors block thisupregulation through the additional blockade ofmTORC2-mediated phosphorylation/activation of AKT, and thusmay represent a more effective strategy to test the effectsof mTOR inhibition (29). A recent study has also shownthat genetic inhibition of PDK1 can induce melanomaregression (60), supporting the rationale for testing ofPDK1 inhibitors in melanoma as they are developedclinically.

One strategy to achieve significant pathway inhibitionclinically with an acceptable therapeutic index is the useof isoform-specific PI3K inhibitors. Genetic studies inmouse models have shown that the PI3K catalytic sub-unit p110a is predominantly responsible for mediatinggrowth factor signaling from RTKs, but it is largely dis-pensable for pathway activation in tumors with PTENloss. Cells with PTEN loss instead seem to depend largelyon p110b to activate the pathway, drive proliferation,and mediate tumorigenesis in vivo (61, 62). Testing of ap110b-selective inhibitor in a panel of >400 cancer celllines showed significantly greater activity in lines withloss of PTEN than in those with PTEN intact (63).However, despite the overall trend, some PTEN-intactcell lines were sensitive, and a number of PTEN-null celllines were resistant. Clinical testing of two differentp110b-selective inhibitors (GSK2636771, SAR260301)is currently ongoing, with planned analysis of PTEN builtinto both studies (www.clinicaltrials.gov). Other PI3Kisoform-specific inhibitors, particularly BYL719 (p110a)and CAL-101 (p110d), have been well tolerated andshowed clinical efficacy in other cancer types (64). Theuse of a p110a-selective inhibitor may be a rationalapproach, in particular, for tumors with PI3K–AKT path-

way activation mediated by RTKs, but to date there are nopublished experimental data testing this hypothesis inmelanoma.

Another strategy to optimize the therapeutic index ofPI3K–AKT pathway inhibitors is the use of alternativedosing schedules. Multiple studies have shown that induc-tion of apoptosis by BRAF orMEK inhibitors inmelanomacell lines with activating BRAF mutations generally is notobserved until theMAPK pathway has been suppressed for48 to 72 hours (29, 65). In contrast, when PI3K pathwayinhibitors are combined with those agents not only isapoptosis increased but it is also generally induced atmuch earlier timepoints (i.e., 24 hours or less; refs. 29, 55).This suggests that relatively short-term exposure to PI3K–AKT pathway inhibitors may be effective clinically. Thisstrategy is similar to that used conventionally with che-motherapy agents, in which dosing regimens have beendeveloped to deliver the maximally tolerated doses ofagents intermittently (i.e., every 7, 14, or 21 days). Theclinical development of targeted therapies instead hasgenerally used continuous dosing regimens. As one of theconcerns about the clinical development of PI3K–AKTpathway inhibitors has been whether sufficient pathwayinhibition is being achieved, the use of high, intermittentdosing may overcome this hurdle. Indeed, intermittentdosing of the combination of a MEK and a PI3K inhibitorexhibited marked antitumor activity in vivo in multiplexenograft models, including melanoma (66). Althoughthis strategy can be explored empirically in mousemodels,one of the critical challenges to the rational developmentof this strategy is the identification of pharmacodynamicmarkers that correlate with the achievement of clinicallyeffective pathway inhibition by PI3K–AKT inhibitors (67).Notably, PI3K inhibitors generally produce marked inhi-bition of AKT activation at doses that are much lowerthan those that correlate with antiproliferative and/orproapoptotic effects. The identification of targets, and/orthe degree of target modulation, that will correspondto clinical benefit, similar to what has been shown forP-ERK and BRAF inhibitors (68), will facilitate the pre-clinical development and clinical evaluation of candidateagents and dosing regimens.

Feedback Loops and Cross-TalkGrowing experience with effective targeted therapies, par-

ticularly in melanoma with selective BRAF inhibitors, hasshown that compensatory signaling within and betweensignaling pathways can be critical to both clinical activityand the emergence of resistance (69–71). Consistent withthis experience, effective clinical targeting of the PI3K–AKTpathway will likely also need to account for and overcomecomplex feedback loops that blunt the activity of single-target inhibitors against it. The seminal example is thefeedback induction of AKT phosphorylation by mTORC1inhibitors, such as rapamycin and RAD001 (Fig. 2). In thesestudies (72, 73), the mTORC1 complexes were foundto negatively regulate IRS1 at baseline, a critical second

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messenger from the IGF1R to PI3K. mTORC1 inhibitor–mediated relief of this negative loop activates PI3K, AKT, andsometimes ERK (74, 75), promoting cell survival (Fig. 2B).This particular feedback has been shown in a variety ofcancers (72–76) including melanoma (28, 77).

More complex feedback perturbations are generated byPI3K and AKT inhibitors (Fig. 3). In breast, lung, andprostate cancer cell lines, these inhibitors induced theFOXO-mediated transcription ofmultiple RTKs, most com-monly HER3 and IGF1R [78–80 (Fig. 3B)]. Independent

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Figure 2. Feedback signalingfollowing mTORC1 inhibition. A,the baseline status of the PI3Ksignaling cascade, indicatingnegative feedback from p70S6Kto IRS1. B, inhibition of mTORC1blocks the negative feedbackloop, activating IRS1, and leadingto PI3K and AKT activation. C,paradoxical activation of PI3KandAKT in the setting of mTORC1inhibition can be overcome bydual PI3K–mTOR inhibitors,which also inhibit PI3K, or dualmTORC1/2 inhibitors, whichblock mTORC2-mediated AKTactivation.

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Figure 3. Feedback signaling following PI3K, AKT, or dual mTORC1/2 inhibition. A, the baseline status of the PI3K signaling cascade, indicating negativefeedback to RTKs such as HER3 and IGF1R, via inactivation of the FOXO transcription factors by AKT. B, PI3K, AKT, or dual mTORC1/2 inhibitorinactivate AKT, releasing the inhibition of FOXO transcription factors, leading to expression and activation of HER3, IGF1R, and other RTKs, subsequentactivation of PI3K and AKT activation, and potentially other pathways (i.e., RAS–RAF–MEK–ERK). This effect is delayed in vitro by 24 to 72 hours ormore and represents a re-equilibration of the pathway over time. C, the addition of RTK inhibitors can block the compensatory signaling and induce synergywith PI3K, AKT, and/or dual mTORC1/2 inhibitors.





studies showed that these RTKs are capable of transducingsignals to both the PI3K–AKT (78) and the RAS–RAF–MEK–ERK pathways (80), potentially reinforcing mutual onco-genic cross-talk. Only when these RTKs were targeted byRNA interference knockdown or by small-molecule inhib-itors (lapatinib, NVP-AEW541) were these feedback activa-tions extinguished. Indeed, combinations of the PI3K andRTK inhibitors displayed synergy in xenograft models(79–81), supporting their therapeutic value. However, onepoint of contention is whether dual mTORC1/2 inhibitors(also referred to as mTORC catalytic inhibitors) can induceRTKs, as some studies explicitly observe this (72, 80, 81)whereas others do not (78, 79), even in the same cell type.These varied results may be due to differences in whetherthe readout is mRNA or protein, as posttranslational mod-ifications and/or protein turnover rates can result in dis-cordant levels (82, 83), or whether the inhibitor hits boththe mTORC1 and mTORC2 complexes. Regardless, theseoverall results serve as an important caution for the futuredevelopment of PI3K inhibition in melanoma and revealpotential cotargets to suppress the feedback activity (Figs. 2and 3).

Dual PI3K–mTOR inhibitors (84) improve on thesesingle-target agents by providing a built-in inhibition ofthe mTOR feedback loops. Characterization of multipledual inhibitors in melanoma cell lines has shown a potentand durable extinction of pAKT and its downstream targets,matching or even exceeding the effects of combining singlePI3K and mTOR inhibitors (54, 77). Indeed, BEZ235 hasshown preliminary success in various preclinical models,particularly in combination with MEK inhibitors (77, 85,86). Relevantly, in a mouse model of melanoma, thecombination of BEZ235 with the MEK inhibitor AZD6244produced a 37% partial response rate (>30% decrease intumor volume; ref. 87). Various clinical trials are currentlyin progress with this class of drugs, although whetherpharmacokinetic and toxicity issues can be optimizedremains to be seen (88).

The existence of these and other feedback loops suggeststhat pharmacodynamic, mechanistic, and resistance tissue-based studies of PI3K–AKT pathway inhibitors in patientsshould optimally allow for the evaluation of multiplemarkers and/or pathways. Emerging proteomic technolo-gies including phospho-RTK and reverse phase proteinarrays (RPPA) facilitate such analyses by analyzing a largenumber of proteins in individual samples concurrently.Notably, although most experimental work to date exam-ining markers and mechanisms of efficacy and resistancewith PI3K–AKT pathway inhibitors has focused on theeffects and changes observed in tumor cells, it is becoming

clear that anticancer treatments also havemarked effects onthe host, including the immune system and the tumormicroenvironment. In melanoma, the durable efficacy ofimmunotherapies (89) and a growing appreciation of theeffects of MAPK-pathway inhibitors on the antitumorresponse (90–93) mandate examination of the immuno-logic effects of PI3K–AKT pathway inhibitors in this disease.The marked activity of p110d-selective inhibitors inhematologic malignancies, and the long-standing use ofmTORC1 inhibitors (rapamycin) as immunosuppressantsin transplant patients, raises the possibility that strategiesthat target the PI3K–AKT pathway could actually inhibit theantitumor immune response and thus blunt long-termclinical benefit. However, an improved understanding ofantitumor immunology and the differential effects of var-ious PI3K–AKT pathway inhibitors on different immunecell populations (94), coupled with strategies (i.e., isoform-specific inhibitors) that are designed to achieve selectivepathway inhibition in tumors, suggests that this challengewill not be insurmountable.

SummaryThe PI3K–AKT pathway remains an attractive combina-

torial target to improve clinical outcomes in patients withmelanoma. As described, emerging understanding andmodels for this pathway are facilitating the developmentof rational strategies. However, critical challenges remain,including matching patients to the appropriate agents;developing appropriate markers to facilitate efficient andmeaningful evaluation of doses that are achieved safely inpatients; and, ultimately, identifying strategies that achieveacceptable therapeutic indices.

Disclosure of Potential Conflicts of InterestM.A. Davies has commercial research grants from GlaxoSmithKline,

AstraZeneca, Genentech, Merck, Oncothyreon, and Myriad. Also, M.A.Davies is a consultant/advisory board member for GlaxoSmithKline, Gen-entech, and Novartis. No potential conflicts of interest were disclosed by theother author.

Authors' ContributionsConception and design: L. Kwong, M.A. DaviesWriting, review, and/or revision of the manuscript: L. Kwong, M.A.Davies

Grant SupportM.A. Davies is supported by NIH 1R01CA154710-01, a Melanoma

Research Alliance Young Investigator Award, an American Society of ClinicalOncology Career Development Award, and Cancer Prevention Institute ofTexas RP120505.

Received April 20, 2013; revised June 21, 2013; accepted July 31, 2013;published online October 2, 2013.

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2013;19:5310-5319. Clin Cancer Res Lawrence N. Kwong and Michael A. Davies in MelanomaNavigating the Therapeutic Complexity of PI3K Pathway Inhibition

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CCR FOCUS · Navigating the Therapeutic Complexity of PI3K Pathway Inhibition in Melanoma Lawrence N. Kwong1 and Michael A. Davies2,3 Abstract Melanoma is entering into an era of