Mammalian target of rapamycin (mTOR) is a component
of the phosphatidylinositol 3-kinase (PI3K) cell survival pathway
that monitors the availability of nutrients, mitogenic signals and
cellular energy and oxygen levels, and therefore is significant in
the regulation of cell growth and proliferation (1). Abnormal activation of the PI3K pathway
is considered to be involved in numerous cancers, and increased
activation of this pathway is often associated with resistance to
cancer therapies (2,3). mTOR acts upstream and downstream of
Akt, operating at a key junction in the PI3K pathway (4). mTOR can form two different
multiprotein complexes, mTORC1 and mTORC2, that regulate the
protein synthesis necessary for cell growth and proliferation
(4–6). Targeted molecular therapy has an
established benefit when combined with platinum-based chemotherapy
in phase III randomized trials of patients with metastatic
non-small cell lung cancer (NSCLC) (7). Agents targeting vascular endothelial
growth factor and epidermal growth factor receptor (EGFR) mimic
several novel targeted approaches that improve survival in patients
with lung cancer. Tyrosine kinase (TK) inhibitors, including
erlotinib and gefitinib, block the intracellular TK domain of EGFR
and subsequently cause a blockade of downstream signaling (8). During the process of identifying novel
agents, studies have focused on characterizing relevant signaling
pathways downstream from surface receptors. A previous study has
reported that mTOR is a crucial component of such pathways
(9).
Ligand-bound activation of one of the transmembrane
receptors leads to the activation of PI3K (10,11).
PI3K subsequently phosphorylates Akt, which is dephosphorylated by
PTEN (12,13). Loss of PTEN is connected with a
diminished prognosis in NSCLC, likely due to the enhanced
downstream signaling of the PI3K/Akt/mTOR pathway (14). The two mTOR complexes, mTORC1 and
mTORC2, are each involved in cell growth (15,16).
mTORC1, which consists of mTOR, Raptor, GβL (mammalian lethal with
SEC13 protein 8) and domain-containing mTOR-interacting protein
(DEPTOR), is partially inhibited by rapamycin (17); it unifies multiple signals that
indicate the availability of growth factors, nutrients and energy
in order to promote cellular growth and catabolic processes during
stress (18,19). Growth factors and hormones, such as
insulin, use Akt to signal mTORC1, which inactivates tuberous
sclerosis complex 2 to prevent inhibition of mTORC1 (20). Active mTORC1 exerts numerous
downstream biological effects, including the translation of mRNA by
phosphorylating downstream targets, such as 4E-BP1 and p70 S6
kinase, the suppression of autophagy through Atg13 and ULK1,
ribosome biogenesis, and activation of transcription that leads to
increased mitochondrial activity or adipogenesis (21–23).
mTORC2, which consists of mTOR, Rictor, GβL, Sin1, PRR5/Protor-1
and DEPTOR, promotes cell survival through the activation of Akt
(24,25). mTORC2 regulates cytoskeletal
dynamics, and ion transport and growth by activating PKCα and
phosphorylating SGK1, respectively (26–28).
mTOR is a downstream target of EGFR and MET signaling, and is
therefore considered to be a therapeutically attractive target for
the treatment of various types of cancer.
Numerous preclinical studies have suggested that
mTOR and associated kinases are significant in the development of
lung cancer. In a previous study, a spectrum of murine lung tissue
was assessed, including normal lung, atypical alveolar hyperplasia,
adenoma and adenocarcinoma tissues obtained from K-ras mice
(29). Immunohistochemical staining
for p-S6 was performed, revealing an elevated level of p-S6 present
at each stage of the progression of malignancy. Subsequent studies
have suggested that treatment with mTOR inhibitors leads to a
reduction in the size and number of early neoplastic lesions. Other
studies have investigated the activity of mTOR itself and the
upstream regulator Akt (30). Using
tissue microarray (TMA) constructs that included >100 specimens
from patients with NSCLC, positive staining for mTOR was exhibited
in ~74% of tumors. The literature contains data indicating the
efficacy of TKIs when EGFR mutations are present, and there are
also studies that have reported an involvement of K-ras mutations
in conferring resistance to EGFR-targeting monoclonal antibodies
(31–35). In an analysis of TMA constructs
containing 37 lung tumors, mTOR activation was identified in 89% of
tumors bearing K-ras or EGFR mutations (36). Another preclinical study examined
the effect of a combined blockade of MEK and mTOR (37) as MEK activation intersects with mTOR
activation at a number of levels. There have been numerous reports
of preclinical data that supports the combination of erlotinib with
an mTOR inhibitor (38–45). In one study, 22 cell lines from four
tumor types, NSCLC, breast, pancreatic and colon tumors, were
assessed and it was revealed that mutations in PTEN, EGFR, PI3K and
K-ras were present in each cell line (46).
Numerous mTOR inhibitors have been revealed to
provide antitumor effects in lung cancer. A two-part phase I study
assessed the antitumor activity, toxicity and pharmacokinetics of
everolimus, administered weekly in 5–30 mg doses, at increased
weekly doses of 50–70 mg and daily administration. In total, 92
patients participated in this study (47), 12 of whom suffered from NSCLC and
two from SCLC. Compensatory tolerance of everolimus doses of ≤70 mg
per week or 10 mg daily was observed. Toxicities, including
stomatitis and fatigue, were observed in one patient, dosed at 50
mg per week and hyperglycemia was observed in another patient,
dosed at 10 mg per day. Partial responses were observed in four
patients and four patients exhibited progression-free survival
(PFS) of ≥6 months.
Following this trial, an additional phase II trial
enrolled patients with NSCLC into two arms: Arm 1 comprised
patients that exhibited a performance status (PS) <2 and had
failed <2 cycles with platinum based therapy and arm 2 comprised
patients that had undergone <2 cycles of platinum based therapy
in combination with an EGFR antagonist. These patients were
administered everolimus at a dose of 10 mg daily. Partial response
(PR) was reported in 5.3% of arm 1 patients and 2.8% of arm 2
patients. The median PFS was 11.3 weeks for arm 1 and 9.7 weeks for
arm 2 patients. The observed toxicities were stomatitis, cough and
dyspnea (48).
Another phase II study investigated patients with
SCLC. The patients were free from brain metastasis, had relapsed
following one or two regimens and exhibited a PS <2. Everolimus
was administered until the disease progressed or until the onset of
unacceptable toxicity. Of the 16 patients, three exhibited stable
disease and the remaining patients exhibited progression.
Everolimus was well tolerated, however, the efficacy of the drug
was low (49). An additional phase
II study assessed the effectiveness of temsirolimus alone in
patients with SCLC, following treatment with four or six cycles of
platinum-based therapy with etoposide or irinitecan (50). Temsirolimus was intravenously
administered weekly at a dose of 25 mg (arm A) and 250 mg (arm B)
until disease progression was observed. In 85 patients, the overall
survival for arm A was 6.6 months and 9.5 months for arm B.
Deferolimus, a non-prodrug rapamycin analogue, was
administered in a phase I trial. In total, 32 patients were
administered with 3–28 mg of deferolimus daily. The maximum
tolerated dose was 18.75 mg. Of the five patients with NSCLC
included in the study, only one exhibited PR (51). An additional phase I study assessed
treatment with gefitinib and everolimus in patients with
progressive NSCLC. Gefitinib was administered at a dose of 250 mg
daily and everolimus was administered at a dose of 5–10 mg daily.
Of the eight patients evaluated, two exhibited PR (52). Following this, a phase II trial was
designed for patients who were previous smokers with stage IIIB/IV
NSCLC (53). The study comprised
untreated patients (arm A) and patients who had previously received
a platinating agent and docetaxel (arm B). PR was observed in 17%
(arm B) of the patients. The toxicities identified were diarrhea,
mucositis and rash. In another phase I trial, the combination of
everolimus with erlotinib was investigated. This cohort consisted
of patients with advanced NSCLC who had previously received two
chemotherapy regimens and had an ECOG PS<2. Patients were
excluded from the trial if they had been previously treated with an
EGFR inhibitor. A standard six and six dose escalation design was
administered with daily doses of 2.5 and 5 mg and weekly doses of
30 and 40 mg of everolimus, combined with 75, 100 and 100 mg of
erlotinib daily. However, the response data of this trial were
moderate (54).
All of the aforementioned preclinical and clinical
trials revealed significant positive results for the use of mTOR
antagonists in lung cancer. mTOR expression may be upregulated by
numerous mechanisms in the pathogenesis of lung cancer.
Furthermore, preclinical data suggests that this class of mTOR
pathway antagonists exert an antitumor effect in lung cancer
therapy. Consistent with this, initial clinical trials of mTOR
inhibitors suggest that they are effective in NSCLC and small cell
lung carcinoma therapy. Several phase II and III trials are
currently in progress. These additional clinical trials are
required to assess the efficacy of mTOR inhibitors as targeted
therapy for NSCLC.
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