Targeting signaling pathways in lung cancer therapy

Abstract

Understanding the oncogenic signaling pathways and their underlying mechanisms may lead to new opportunities for developing therapeutic strategies for cancer treatment. In recent years, some molecular targeted agents have emerged for the inhibition of specific targets in signaling pathways. There are also studies examining whether the combination of these pathway-based therapeutics with standard therapies can produce synergistic effects in lung cancer treatment. On the other hand, it has been reported that some predictive biomarkers have been identified for the triage of patients most likely to benefit from these targeted drugs. This article discusses the features and targeting of some dysregulated signaling pathways in lung cancer therapy intending to provide up-to-date information of the recent discoveries in lung cancer signaling pathway research and the most promising developments of pathway-based therapies, which may lead to substantial improvements for the clinical treatment of lung cancer.

Keywords::

• EGFR
• lung cancer
• mTOR
• signaling pathway
• VEGF
• Wnt

1. Introduction

Genomic mutations of cancer cells dysregulate the signaling pathways with a critical position in cell growth, proliferation, angiogenesis, apoptosis, and metastasis [1]. Because signaling pathways play a prominent role in the formation and progression of lung tumors, extensive studies are devoted for the investigation of drugs that target molecular alterations to interfere with signaling pathways specific to this unique malignancy. This article outlines the main signaling pathways involved in the development and progression of lung cancer and the agents that target these pathways. Finally, the current status and future perspective will also be discussed.

2. Targeting signaling pathways in lung cancer therapy

The molecular mechanisms involved in the development and progression of lung cancer are complex. Genetic and epigenetic changes occur after chronic inflammation and cigarette smoking exposure, including oncogene activation and tumor suppressor gene inactivation due to oxidative stress-induced DNA damage. Through apoptosis and cell proliferation, these changes lead to the multistep development and progression of lung cancer. A number of studies have reported changes in gene expressions and molecular abnormalities involved in signaling pathways. Some molecular targeted agents have emerged for the inhibition of specific targets among the dysregulated signaling pathways in lung cancer (Table 1).

Table 1. Some core signaling pathways in lung cancer.

Pathway	Molecular target	Targeted drug	Potential marker	Refs.
Wnt/β-catenin	DACT2 DSP	sLRP6E1E2	–	[2-4]
mTOR	Na^+/K^+-ATPase	Everolimus	–	[5-7]
VEGF	VEGF	Bevacizumab Pazopanib Vandetanib	CAF	[8-13]
EGFR	EGFR	Afatinib Cetuximab Dacomitinib Erlotinib Gefitinib	EGFR	[14-20]
Metabolic	Glycine decarboxylase	–	–	[21,22]

CAF: Cytokine and angiogenic factor; DACT2: Disheveled-associated antagonist of β-catenin 2; DSP: Desmoplakin; EGFR: Epidermal growth factor receptor; mTOR: Mammalian target of rapamycin; VEGR: Vascular endothelial growth factor.

2.1 Wnt/β-catenin signaling pathway

Disheveled-associated antagonist of β-catenin 2 (DACT2) is a key component of the Wnt signaling pathway and its methylation was found to be associated with poor differentiation of human lung cancer. It has been reported that DACT2 was silenced by promoter region hypermethylation and it inhibited lung cancer proliferation by suppressing the Wnt signaling pathway [2]. The expression of a key component of desmosomal plaque proteins, desmoplakin, was also reported to have antitumorigenic activity in non-small cell lung cancer (NSCLC). Desmoplakin was inactivated in NSCLC by epigenetic mechanism and it increased the sensitivity to anticancer drug-induced apoptosis with its tumor-suppressive function possibly through inhibition of the Wnt/β-catenin signaling pathway [3]. As aberrant activation of the Wnt pathway contributes to cancer progression, a Wnt antagonist sLRP6E1E2 has been developed. It induced apoptosis, cytochrome c release, as well as increased cleavage of PARP and caspase-3. In addition, sLRP6E1E2 suppressed growth of the human lung tumor xenograft, and reduced motility and invasion of cancer cells by inhibiting interaction between Wnt and its receptor [4].

2.2 Mammalian target of rapamycin signaling pathway

Na⁺/K⁺-ATPase targeted lung cancer therapy has attracted increasing interests and cardiac glycosides can act as Na⁺/K⁺-ATPase inhibitors. Cardiac glycosides were found to induce moderate G₂/M arrest but not apoptosis at IC₅₀ level in the NSCLC cells. They induced autophagy through deactivation of the mTOR signaling pathway and activation of the extracellular-signal-regulated kinase 1/2 signaling pathway [5]. Indeed, mTOR is a promising target of lung cancer and everolimus is an inhibitor of the mTOR pathway. A Phase II study of everolimus was conducted in previously treated small cell lung cancer. Everolimus (10 mg orally daily) was well tolerated but had limited single-agent antitumor activity in unselected previously treated patients with relapsed small cell lung cancer. Further evaluation in combination regimens for patients with sensitive relapse may be considered [6]. A Phase I and pharmacokinetic study of docetaxel and everolimus was also conducted for recurrent NSCLC. Promising anticancer activity has been noted this time. The daily recommended Phase II doses of docetaxel and everolimus for combination therapy are 60 mg/m² and 5 mg orally [7].

2.3 Vascular endothelial growth factor signaling pathway

Targeting the VEGF pathway in earlier-stage disease may be beneficial in patients with NSCLC. Pazopanib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) that blocks tumor growth and inhibits angiogenesis. A Phase II trial has been performed to examine the safety and efficacy of preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC. Short-duration pazopanib demonstrated to be generally well tolerated and 86% of patients achieved tumor-volume reduction. These data suggest that pazopanib merit further clinical evaluation in NSCLC [8]. There was a study conducted on plasma cytokine and angiogenic factor (CAF) profiling to investigate the relationship between baseline CAF levels and tumor shrinkage in early-stage NSCLC patients treated with pazopanib. Baseline levels of IL-12 showed a strong association with tumor shrinkage. A baseline CAF signature consisting of hepatocyte growth factor and IL-12 was associated with tumor response to pazopanib and it identified responding patients with 81% accuracy. Further investigation of this potential predictive marker for pazopanib in clinical trial is warranted [9].

Vandetanib is another oral TKI that inhibits epidermal growth factor receptor (EGFR or HER1) and VEGF receptor. A Phase III trial (ZEPHYR) assessed the efficacy of vandetanib for patients with advanced NSCLC after prior treatment with an EGFR-TKI. Disappointingly, this study did not demonstrate an overall survival benefit for vandetanib versus placebo and there was a higher incidence of some adverse events with vandetanib [10]. Therefore, there is a need to discover biomarkers for the identification of patients who will likely to benefit from vandetanib monotherapy. A Phase II trial was performed to analyze the plasma CAFs from patients with NSCLC who received vandetanib therapy. Cytokine and angiogenic factor profiling observed that VEGF was associated with increased progression risk, whereas increase in intercellular adhesion molecule 1 was associated with decreased risk [11].

Bevacizumab is a monoclonal antibody that also targets VEGF in NSCLC. The administration of this agent is postulated to decrease nitric oxide synthesis and lead to hypertension. Data from a Phase III trial (ECOG 4599) of bevacizumab in combination with carboplatin and paclitaxel for the treatment of patients with nonsquamous NSCLC suggest that the onset of high blood pressure during this combination therapy may be a physiological sign that the VEGF pathway is more actively being blocked and this may result in improved outcomes [12]. Another Phase III trial (BeTa) assessed whether bevacizumab plus erlotinib conferred a survival benefit in advanced NSCLC after failure of standard first-line chemotherapy. Regrettably, the addition of bevacizumab to erlotinib did not seem to improve survival in patients with recurrent or refractory NSCLC [13].

2.4 EGFR signaling pathway

Mutations of EGFR and its family members (ErbB2 or HER2, ErbB3 or HER3, and ErbB4 or HER4) are associated with a number of cancers, including lung cancer. Afatinib is an irreversible ErbB-family blocker with preclinical activity in NSCLC with EGFR mutations. In a Phase II trial, afatinib showed antitumor activity in the treatment of advanced lung adenocarcinoma patients with EGFR mutations, particularly in those with deletion 19 or L858R mutations [14]. Dacomitinib is another irreversible pan-human EGFR inhibitor. A Phase II trial compared dacomitinib with erlotinib (a reversible EGFR inhibitor) in patients with advanced NSCLC. With acceptable toxicity, dacomitinib demonstrated a significant improvement in progression-free survival (PFS) versus erlotinib, especially in patients with EGFR mutants or KRAS wild-type [15].

The US Food and Drug Administration has approved erlotinib for the treatment of locally advanced or metastatic NSCLC that has failed at least one prior chemotherapy regimen. A Phase III study (OPTIMAL) compared the tolerability and efficacy of erlotinib versus standard chemotherapy in the first-line treatment of advanced NSCLC patients with EGFR mutations (deletion 19 or L858R). Erlotinib conferred more a favorable tolerability and significant PFS benefit in patients with advanced EGFR mutation-positive NSCLC [16]. Another Phase III trial (TORCH) was designed to test the efficacy of first-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced NSCLC. In unselected patients with advanced NSCLC, this first-line erlotinib followed by second-line chemotherapy regimen was significantly inferior in terms of overall survival compared with the standard sequence of first-line chemotherapy followed by erlotinib [17].

There was also a Phase III study (TITAN) that assessed the efficacy of second-line erlotinib versus docetaxel or pemetrexed in patients with recurrent or metastatic NSCLC. In unselected patients with refractory NSCLC during or immediately after first-line platinum doublet chemotherapy, no significant differences in efficacy were noted between patients treated with second-line erlotinib and those treated with second-line chemotherapy [18]. Gefitinib is another EGFR-TKI that may be used as maintenance therapy in patients with advanced NSCLC. A Phase III trial (INFORM) investigated the efficacy of gefitinib in the maintenance setting. This EGFR-TKI significantly prolonged PFS compared with placebo in patients from East Asia with advanced NSCLC who achieved disease control after first-line platinum-based doublet chemotherapy [19].

With different outcomes from the clinical trials of EGFR inhibitors, there is increasing pressure to identify predictive biomarkers that may help to guide the therapeutic decisions for NSCLC treatment. Cetuximab is an anti-EGFR monoclonal antibody drug. To define patients benefiting most from cetuximab, the association of tumor EGFR expression level with clinical outcome in a Phase III study (FLEX) was analyzed. High EGFR expression has been identified to be a tumor biomarker that can predict survival benefit from the addition of cetuximab to cisplatin and vinorelbine in the first-line treatment of patients with advanced NSCLC. Assessment of EGFR expression may offer a personalized treatment approach in this setting [20,21].

2.5 Metabolic signaling pathway

Genetic events in cancer activate signaling pathways that affect tumor cell metabolism. Clinical data has suggested the possible link between cancer cell metabolisms with treatment outcomes. In recent years, there has been an increasing interest in the study of how changes in cell metabolism promote tumor growth [22]. Emerging evidence has revealed a correlation between the expressions of metabolic enzymes with the risk of lung malignancies. For example, a recent study has reported that glycine decarboxylase was overexpressed in NSCLC. The overexpression of glycine decarboxylase promoted cellular transformation and tumorigenesis, leading to changes in glycine metabolism to regulate cancer cell proliferation [23]. Thus, xenobiotic metabolizing enzymes may be a new metabolic target for the treatment of lung cancer.

3. Expert opinion

The advances in cellular and molecular biology have clarified the mechanisms involved in cancer growth, invasion, and metastasis. The discoveries of various molecular pathways in lung cancer represent a significant breakthrough for the treatment of this heterogeneous cancer not previously experienced. Many molecular targeted agents are now under development and trial to target the growth factor receptors and signaling pathways in lung cancer. Because the main treatment option for metastatic and advanced-stage lung cancer is systemic chemotherapy, clinical trials have been conducted to investigate the combined efficacy and relative merits of these molecular targeted agents with standard therapies. Studies and clinical trials to identify and test predictive biomarkers for these drugs are also ongoing. Although the investigations of signaling pathways and the development of agents targeting these pathways are making steady progress, many issues remain to be addressed. It is necessary to expand the knowledge of the role and mechanisms of different signaling pathways in lung cancer therapy. Close attention should also be paid to the limit and adverse effects associated with the molecular targeted agents currently under development. Clinical trials should be conducted to identify which molecular targeted agents should be used as initial or second-line therapy. Nevertheless, the approval of a number of pathway-based therapies in recent years is undoubtedly the beginning of a paradigm shift of lung cancer treatment.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.