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Mtor Co-Targeting Strategies for Head and Neck Cancer Therapy

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Mtor Co-Targeting Strategies for Head and Neck Cancer Therapy Cancer Metastasis Rev (2017) 36:491–502 DOI 10.1007/s10555-017-9688-7 mTOR co-targeting strategies for head and neck cancer therapy Zhiyong Wang1,2 & Juan Callejas Valera1 & Xuefeng Zhao1,2 & Qianming Chen2 & J. Silvio Gutkind1 Published online: 18 August 2017 # The Author(s) 2017. This article is an open access publication Abstract Head and neck squamous cell carcinoma (HNSCC) combination of mTOR inhibitors and immune oncology is the sixth most common malignancy worldwide. There is an agents may provide novel precision therapeutic options for urgent need to develop effective therapeutic approaches to HNSCC. prevent and treat HNSCC. Recent deep sequencing of the HNSCC genomic landscape revealed a multiplicity and diver- Keywords mTOR . Head and neck cancer . Precision sity of genetic alterations in this malignancy. Although a large therapy . Immune oncology variety of specific molecules were found altered in each indi- vidual tumor, they all participate in only a handful of driver signaling pathways. Among them, the PI3K/mTOR pathway 1 Background is the most frequently activated, which plays a central role in cancer initiation and progression. In turn, targeting of mTOR Head and neck squamous cell carcinoma (HNSCC) is the may represent a precision therapeutic approach for HNSCC. sixth most common malignancy worldwide. As a major public Indeed, mTOR inhibition exerts potent anti-tumor activity in health concern, HNSCC arises in the oral cavity, larynx, and HNSCC experimental systems, and mTOR targeting clinical pharynx, affecting approximate 600,000 patients each year trials show encouraging results. However, advanced HNSCC [1], only 40–50% of which will survive more than 5 years patients may exhibit unpredictable drug resistance, and the [2]. The leading risk factors include the use of tobacco, alco- analysis of its molecular basis suggests that co-targeting strat- hol, and betel quid and areca nut chewing, while high-risk egies may provide a more effective option. In addition, al- human papillomavirus (HPV) infection has emerged as a ma- though counterintuitive, emerging evidence suggests that jor risk factor, nowadays accounting for more than 20% of all mTOR inhibition may enhance the anti-tumor immune re- HNSCC cases [3]. Currently, the main therapeutic modalities sponse. These new findings raise the possibility that the include surgery, radiation, and chemotherapy. However, these nonselective treatments may cause associated morbidity and mortality and usually have high systemic toxicities. Cetuximab, a monoclonal antibody-inhibiting EGFR, is the Zhiyong Wang and Juan Callejas Valera contributed equally to this work. only cancer-targeting agent approved for HNSCC, although only ~10% of HNSCC patients respond to this agent and often * Qianming Chen for a short period of time [4, 5]. Two immune check point [email protected] inhibitors targeting PD-1 have been recently approved by * J. Silvio Gutkind the FDA for HNSCC patients, albeit the rate of response is [email protected] approximately 20%, lower than that of other malignancies, such as melanoma [6–14]. There is an urgent need to develop 1 Moores Cancer Center, University of California San Diego, La Jolla, CA, USA new effective strategies to prevent and treat HNSCC. Understanding the contribution of genomic alterations driving 2 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology, HNSCC initiation and progression may help explore novel Sichuan University, Chengdu, Sichuan 610041, China precision therapeutic options. 492 Cancer Metastasis Rev (2017) 36:491–502 2 Genomic landscape in head and neck cancer genomic alterations causing the persistent activation of PI3K/AKT/mTOR pathway in HNSCC. Various genetic and Deep sequencing approaches for the study of cancer genomes epigenetic changes coordinate with PI3K mutations to sustain have recently revolutionized medical oncology [15]. By pro- activation of this pathway in HNSCC (Fig. 1). viding an unprecedented knowledge of the multiplicity and For instance, DNA copy number gain and messenger RNA diversity of genomic and epigenetic alterations which underlie (mRNA) overexpression of PIK3CA frequently occur in every individual cancer lesion, these approaches deepen the HNSCC (20 and 52%, respectively). Other PI3K isoforms understanding of dysregulated signaling circuitries and molec- and multiple PI3K regulatory subunits also have mutations ular mechanisms driving cancer development. Based on these and copy number gains (0.5–11%). Over 90% of HNSCC information, novel druggable targets for therapeutic interven- lesions overexpressed the epidermal growth factor receptor tions in various human malignancies have been revealed. (EGFR), which is upstream of PI3K/AKT signaling, a major Several recent reports [16–19] and a landmark study from driver of epithelial cell proliferation. And a low frequency of the Cancer Genome Atlas (TCGA) Network [1] has provided HNSCC cases has mutations in AKT2 and mTOR or its regu- a comprehensive genomic characterization of HNSCC, re- latory subunits, RICTOR and RAPTOR. A network-based vealing hundreds of mutations in each HNSCC lesion. This analysis of the HNSCC oncogene revealed that a high percent- complexity of genomic alterations makes it daunting to search age of lesions also exhibit loss of at least one copy of a can- for molecular events driving the development of cancer, espe- didate PI3K/mTOR pathway tumor suppressor gene (TSG), cially to differentiate driver from passenger mutations, the PTEN (31%), TSC1 (11%), TSC2 (13%), STK11 (34%), and latter having a minimal influence on tumor progression and/ EIF4EBP1 (36%) [20]. Interestingly, co-occurrence of their or therapeutic response. However, in-depth analysis of the gene loss is a highly statistically significant event (Table 1). HNSCC oncogenome suggests that despite the complexity Similarly, PIK3CA amplification co-occurs in a highly statis- of the distinct molecular alterations in individual lesions, they tically significant fashion with gene copy gains in PI3KCB, all fall within a limited number of dysregulated molecular encoding the PI3Kβ subunit. These occurrences of multiple pathways that may contribute to most HNSCC patients [1, 3]. alterations may cooperate to persistently activate PI3K/AKT/ Specifically, the most frequently identified alterations in mTOR pathway in most HNSCC lesions. HNSCC participate in biologic processes regulated by the HPV infection has been recently recognized as a viral eti- TP53 (71% mutated), FAT1 (23% mutated and 5% deleted), ologic agent responsible for HNSCC, more specifically in the NOTCH1 (9% mutated and 66% signaling pathway alter- oropharynx [21, 22]. While the overall incidence for HNSCC ations), CASP8 (10% mutated), CDKN2A (22% mutated and continues to decrease, it is observed that the incidence of 60% gene copy loss) genes, and PIK3CA (~20% mutated and HPV-associated HNSCC has a highly significant increase, 30% signaling pathway alterations) [3]. This reductionist ap- predominantly among young patients [23–25]. Among the proach based on comprehensive genomic profiling may be viral proteins encoded by high-risk HPVs (HPV16 primarily exploited to distinguish oncogenic signaling-related subgroups in HNSCC), E6 and E7 function as major driver oncogenic from unselected cancer cohorts and facilitate the identification proteins. By disrupting p53 and RB tumor suppressor pro- of actionable therapeutic targets for HNSCC patients. teins, respectively [26–28], E6 and E7 induce malignant trans- formation. Recent findings suggest that HPV+ HNSCC has a significant enrichment of PIK3CA mutations (25% more than 3 Activation of PI3K-mTOR signaling pathway HPV−) and exhibit elevated mTOR activity [1, 29–31]. Of in head and neck cancer note, E6 and E7 oncoproteins could not be therapeutically targeted so far, making it essential to explore druggable targets A more pathway-specific analysis of the HNSCC for HPV+ HNSCC, in which mTOR inhibition provides suit- oncogenome suggests that most genomic alterations are in- able therapeutic options [31]. volved in aberrant mitogenic signaling routes, including the Taken together, the above findings suggest that, although PI3K, MAPK, and JAK/STAT pathways [17]. Remarkably, genomic alterations found in HNSCC varies and are remark- the PI3K-mTOR pathway is mutated in the highest percentage ably complex, most fall within certain oncogenic pathways, of the cases. In contrasts, MAPK and JAK/STAT pathways most of which result in persistent aberrant activation of the harbor mutations in less than 10% of the lesions. Specifically mTOR signaling pathway. for PI3K, the in-depth analysis of TCGA data from 428 HPV− and 76 HPV+ HNSCC samples [20]revealedthatPIK3CA is the highest mutated gene when considering all HNSCC cases 4 The roles of mTOR signaling pathway in cancer (16.8%), and PI3K mutations (PIK3CA, PIK3CB, PIK3CG, and PIK3CD) are frequently mutated genes in 30% of the The mTOR (mechanistic target of rapamycin) pathway regu- HPV+ lesions. Moreover, PI3K mutations are not the only lates major cellular processes involved in organismal growth Cancer Metastasis Rev (2017) 36:491–502 493 M: gene mutation EGFR PIK3CA PIK3R1(p85 ) G: copy number gain ( ≥2 ) M: 4.2 (2.6)% M: 16.8 (25)% M: 1.2 (5.3)% L: copy number loss, EGFR G: 12.1 (1.3)% G: 20.1 (27.6)% hetero (-1) or homozygous (-2) PIK3CB P P p85 p110 PIP3 P110 / / M: 1.4 (1.3)% RAS G: 11 (7.9) % P P PDK1 P P P PIK3CG HRAS M: 3.7 (1.3)% M: 6.5(0)% PTEN G: 3.3 (0) % G: 0.7 (0)% AKT P AKT1 PTEN T308 M: 4 (3)% PIK3CD M: 1.4 (2.6)% M: 2.1 (6.6)% P S473 L: 26.2 (34.2)% G: 0.5 (0) % TSC2 P M 1.6 (1.3)% TSC2 L 13.8 (11.8)% STK11 (LKB1) PRKAA1/2 TSC1 Rheb TSC1 M 0.7 (4)% (AMPK1/2) M 0.7 (1.3)% RICTOR L 36 (17)% M: 1% L 13.3 (5.3) % M 1.6 (2.6)% mTORC1 G: 6.3 (1.3) % LKB1 AMPK P mTOR rictor mTOR raptor RAPTOR M 1.4 (1.3)% mTORC2 G 0.2 (1.3) % MTOR M 4 (3)% P P EIF4EBP1 4E-BP1 S6K RPS6KB1(S6K) M 0.2 (0)% M 0.9 (1.3)% L 39.5 (9.2)% G0 (1.3)% RPS6KB2(S6K) P P M 0.2 (1.3)% EIF4E G 6.5 (5.3)% M 0.2 (0)% elF-4E S6 Fig.
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