Current and Future Targeted Therapies for Non-small-cell Lung Cancers With Aberrant EGF Receptors

Shanthi Kanthala; Sandeep Pallerla; Seetharama Jois


Future Oncol. 2015;11(5):865-878. 

In This Article

Conclusion & Future Perspective

Lung cancer has always been viewed as one of the most difficult cancers to treat. To make treatment more complicated, the incidence of lung cancer rises substantially with age. Only about one-third of cases develop below the age of 65 years; the majorities of patients are 65 years and over, with the median age of onset around 70 years. The general strategy of cancer therapy that involves surgery to remove as much of the tumor as possible and then treat with chemotherapy or radiation therapy to remove the remaining cancer tissue does not apply to lung cancer treatment.[77,78] This is because, in the case of lung cancers, tumors are diagnosed after the cancer has already spread past the lungs. As a result, surgery alone very rarely leads to a cure; pulmonary function and age complicate the option of surgery and, thus, most patients are unfortunately not even candidates for surgery. The opportunity to detect the cancer early means that more individuals could be cured by surgical excision or radiation therapy. Either of these can be followed by adjuvant chemotherapy for those with a high likelihood of microscopic disease spread. Since smoking is related to lung cancer, one of the ways to reduce the number of lung cancer patients is to reduce smoking. The result of reduced smoking has not been clear as yet, since a high percentage of lung cancer is seen in individuals who are only casual smokers or former smokers and the risk of lung cancer does not seem to decline for many years following smoking cessation (American Cancer Society Facts and Figures 2013[79]).

In the past ten years, the EGFR family has gained significance in NSCLC biology and has become a key focus of targeted therapies. There is no doubt that personalized therapy for advanced NSCLC has been improved by the introduction of the TKIs gefitinib and erlotinib. However, TKI therapy is limited by the development of resistance in most of the patients that are treated. Hence, several efforts are being undertaken to understand the mechanisms of resistance in order to develop combination treatments capable of sensitizing cells resistant to EGFR TKIs. Despite the number of possible drugs and treatments available for lung cancer therapy, lung cancer still results in the largest number of cancer-related deaths worldwide of which more than 85% are from NSCLC.[80] In 2001, the overall 5-year survival rate was 14% for lung cancer.[81] After nearly a decade, the predicted overall 5-year survival rate was 15.9%. Although saving each patient is considered remarkable in cancer treatment, a decade of improvement in science and technology has only marginally improved the therapeutic effects in lung cancer. The major reasons for this are the development of resistance to most of the TKI or antibody treatments and the heterogeneity of the disease.[6] In addition, lung cancer treatment is complicated by the fact that most patients do not exhibit any symptoms until the cancer has spread too far to be cured. In addition to therapy for lung cancer tumors, patients need improved quality of life as they suffer from airway obstruction. In many cases, bulky endobronchial disease or extrinsic compression of the major airways results in significant difficulty in maintaining a good quality of life during treatment.[82]

There has been significant progress in recent years in the area of lung cancer diagnosis and treatment. Further, there has been progress in treatment with combination drug therapies after radiation therapy and with new compounds targeted at driver mutations.[83] Based on the literature reports and the development of resistance, it is clear that lung cancer treatment, in particular NSCLC treatment, cannot be viewed as 'one-size fits-all' type of therapy. Future treatments will involve individualized therapies based on extensive knowledge about the type of pathological condition the patient exhibits in NSCLC.[84] The pretreatment detection of responsive predictor markers and individualized effective treatments will help to maximize the therapeutic index of lung cancer treatment. The last decade has seen advances in screening procedures using next-generation sequencing,[85,86] large databases of genomics and proteomics for tumor types,[87] and molecular markers and biochemical knowledge of the molecular basis of the development of resistance in terms of mutation. All of these will help physicians and scientists decide how a particular subset of NSCLC can be treated. Future therapies will be based on the mutations found in patients' tumors. In the USA, there is a lung cancer mutation consortium, and in Europe, the International Association for the Study of Lung Cancer, European Thoracic Oncology Platform, and European Respiratory Society have been established; these involve many centers across the USA and Europe.[88] The data generated by these centers can be shared so that any new mutation can easily be screened and an effective therapy can be proposed. The majority of the NSCLC mutations have been observed in EGFR.[89] Several combination therapies proposed are already in clinical trials. One example is EML4-ALK/crizotinib.[90,91] The lung cancer mutation consortium is also conducting a study in which lung cancer tissue is assessed for ten known driver mutations in EGFR, ALK, KRAS, HER2, BRAF, PIK3CA, AKTI, MEKI, NRAS and MET using a multiplex assay. New drug-like molecules targeting these mutations are under development. In the case of HER2 and EGFR overexpression, targeted drugs that are already on the market (such as trastuzumab and lapatinib, which are used in breast cancer) are being evaluated for lung cancer therapy. New TKIs such as afatinib, which was approved in July 2013 for EGFR with mutations, have shown positive results.[21,92] Such pan inhibitors and combination therapies with these pan inhibitors are the future drugs of choice.[55,93] However, all of these treatments require testing of EGFR mutations in patients with NSCLC. In the coming decade, lung cancer therapy will involve screening patients for biomarkers.[94,95]

Possible treatments for lung cancer in the near future include next-generation therapies such as therapeutic cancer vaccines[96–100] and stem-cell treatments[101,102] that will play a major role. Therapeutic cancer vaccines, also known as immunotherapy treatments, are drugs that attempt to teach a patient's immune system to recognize cancer cells so that they can be naturally destroyed. Stem-cell targeting in NSCLS is still in the infancy stage, and much more detail about cancer stem cells has to be studied before drugs can be targeted to stem cells. Protein–protein interactions have also been targeted for lung cancer.[103] These could be interfaces of EGFR proteins or other oncogenic proteins such as BCL1-Beclin 1.[104,105] The targeting molecules could be antibodies, peptides, peptidomimetics or small molecules. Many of these molecules are in the preclinical stages. Our research group has developed new and novel peptidomimetics that target the extracellular domain of HER2 protein, in particular, domain IV of HER2 protein, and inhibit protein–protein interactions of EGFR (Figure 2).[106–108] These are dual inhibitors that inhibit EGFR:HER2 and HER2:HER3. Such dual inhibitors block phosphorylation of EGFR and HER2 and also block the downstream signaling of the MAPK and PI3K pathways. HER2 plays an important role in the dimerization of receptors and phosphorylation and is important in the MAPK and PI3K/Akt pathways. Targeting HER2 and inhibiting EGFR:HER2 and HER2:HER3 dimerization may have a significant impact on HER2-overexpressed lung cancer, in particular, NSCLC. These compounds bind to the extracellular domain and, hence, do not need to be transported into the cells. Furthermore, since these molecules target protein–protein interfaces but not the kinase domain, the probability of developing mutation is less and hence less resistance to the treatment. The development of such molecules as therapeutic agents is yet to be seen.

Figure 2.

Protein–protein interaction inhibition method for the development of drugs for different types of EGF receptor-overexpressed cancer. The extracellular domains of EGFR and HER2 are shown as heterodimers. Note that domain IV is involved in the interaction of two proteins. Domain IV can be targeted with small molecules, peptides or peptidomimetics for the inhibition of dimerization. The region of PPI and its inhibition is marked by an oval shape. The model of EGFR:HER2 heterodimer was generated [108,109] using the crystal structures of EGFR (PDB ID 3NJP) [110] and HER2 (PDB ID) [111] with a homodimer of EGFR as a template (PDB ID 3NJP). EGFR: EGF receptor; PPI: Protein–protein interaction.

Systematic genotypic testing in NSCLC patients for the detection of HER2 and EGFR mutations is crucial for treatment with targeted therapies. The co-overexpression of EGFR and HER2 in NSCLC and the poor survival rate of patients with coexpression of these receptors suggest that EGFR and HER2 should be simultaneously targeted for treatment. Most of the next-generation drugs, including afatinib and neratinib, target both EGFR and HER2. Although there is much research being conducted in this area, there are very few EGFR-targeted therapies available to patients with advanced lung cancer. This may be attributed to challenges encountered in the development process – cost, quick development of resistance, lack of novelty, efficacy versus toxicity and barriers in the late clinical trials. Addressing all of these issues is important for the development of more targeted therapies in the future. The future of lung cancer therapy is a long road compared with that of breast and prostate cancer and depends heavily on genetic screening.