For years, the fundamentals of cancer treatment were surgery, chemotherapy and radiotherapy. In the past two decades, targeted therapies, such as imatinib and trastuzumab, drugs targeting cancer cells by addressing specific molecular changes mainly seen in cancer cells, have also been accredited as standard treatments for many cancers.
From a historical point of view, the specific therapy of cancer cells with the antihormonal estrogen receptor (breast cancer) and the testosterone receptor (prostate cancer) was successful. However, the vulnerable point in the treatment of cancer by targeted therapy was the emergence of genetic mechanisms of drug resistance.
Sequencing of the transgenic genome of tumor DNA has elucidated low-frequency mutations in several genes that are highly susceptible to lead to oncogenesis. For example, mutations in the human genome are about 20%, some of which are so-called “mutation drivers”, many of which are passers-by(1).
The frequency of mutations in genetic families that contribute to cancer has yet to be established. Somatic mutations vary in different types of cancer (e.g., brain, pancreas, colon), as well as in a given tumor type, but appear to use common overlapping oncogenic pathways detected in the malignant phenotype(2,3,4). Imatinib mesylate (IM) is an excellent example of a “small molecule inhibitor” (SMI) targeting a major context of vulnerability to a defined genetic anomaly such as translocation of t (9; 22) (BCR-ABL) into myeloid leukemia chronic (CML) and gastrointestinal stromal tumors (GIST), with a good safety profile.
The HER family
The family of receptors for human epidermal growth factors (HER 1, 2, 3 and 4) consists of RTK that are overexpressed (HER 1, 2 and 3, lung cancer, head and neck, breast and prostate) or mutants (HER 1 and 2, glioblastoma multiforme [GBM]), which lead to constitutive activation in human epithelial malignancies. Among the different dimer pairs, the HER1/HER2 heterodimer is the most potent and activates the RAS-MAPK and STAT pathways, as well as the HER 3 (inactive kinase domain) that activates the PI3K/AKT survival pathway(5). The HER family members were selected as the first molecules for targeted therapy, primarily due to the detection of the HER 2 amplicon on chromosome 17q12-21 in approximately 20% of aggressive breast cancer patients with low prognosis(6).
Trastuzumab, a HER 2 inhibitor monoclonal antibody (MAB), binds the extracellular domain (ECD) IV of HER 2 near the membrane and was developed due to its affinity, specificity and efficacy in breast cancer cell lines at first in mouse models. It is currently approved by the FDA for the treatment of metastatic breast cancer HER 2+ and adventitious in combination with chemotherapy because it has a modest activity when used alone.
A second MAB targeting HER 2 pertussumab (2C4) binds to ECD II and interferes with heregulin (HRG)-induced HER2/HER3 heterodimerisation and thus acts as an ERB2 dimerization inhibitor which may be useful in inhibiting HER 3 overexpressed tumors (prostate, colon, lung) by abrogating the activation of the PI3K/AKT pathway. Since the approval of trastuzumab, the FDA has approved several HER1-directed MABs (cetuximab, panitumumab) that disrupt autocrine loops in human malignancies (colon, head and neck) and have higher responses when combined with chemotherapy(7). Several SMIs of the HER TK domain have also received FDA approval: erlotinib and gefitinib are HER 1 (lung and pancreatic cancer) and lapatinib is a double HER1/HER2 inhibitor (trastuzumab-resistant breast cancer)(8). Pan-HER carnitinib inhibitor and HER 2 selective inhibitor CP-724,714 are undergoing clinical evaluation(9).
Hepatocyte Growth Factor (HGF/SF) activates c-Met, an important RTK for many normal cellular functions. The aberrant signal transmitted through the HGF/MET axis is involved in a variety of human malignancies by increasing invasion, antiapoptosis and neoangiogenesis.
The carcinogen-induced chromosome rearrangement (TPR-MET) in a cell line of osteosarcoma identified MET as a transforming oncogene and subsequently found it in some types of gastric cancer(10). Missing mutations of the c-Met gene are found in type 1 renal papillary carcinoma (RCC) (13%)(11). Most of the latter have trisomy 7, with the nonrandom duplication of the mutant c-Met leading to the transformed phenotype.
Somatic mutations c-Met exist in a variety of other malignancies (gastric, liver, SCLC, NSCLC, H/N SCC)(12), but these are rare. The activation of MET due to genetic amplification and/or overexpression is detected in many human malignancies. Autocrine and aberrant paracrine circuits also contribute to malignant phenotype in many cancers (e.g., breast cancer, sarcoma).
Furthermore, aberrant MET activation is observed in metastatic lesions, but not in the primary tumor (e.g., colon cancer), which may potentiate the acquisition of secondary somatic mutations (Y1230C; Y1235D) during metastases (e.g., headache/neck)(13). Therefore, oncogenic signaling in certain types of cancer due to “dependence” (mutations) or survival advantage (overexpression) provides a convincing reason for targeting therapy to the HGF/MET axis.
EGFR driver mutations have long been studied with non-smal lung cancer. Several randomized trials, including EURTAC(14) and OPTIMAL(15) for erlotinib; NEJGSG_ 002(16), WJTOG 3405(17) and IPASS(18) for gefitinib; and LUNG LUNG 3(19) and LUX LUNG 6(20) for afatinib demonstrated the superiority of EGFR TKIs to chemotherapy in terms of overall response rates and progression-free survival (PFS).
Erlotinib and gefitinib are the first generation of reversible TKI, whereas afatinib and lapatinib are the second generation of pan-HER TKI(21) irreversible, which are reported to be superior to gefitinib in EGFR 19 exon 19 and other uncommon mutations.
Despite the initial rates of response with these TKIs, the development after 11-14 months of acquired resistance as defined by the Jackman criteria(22) (disease progression after objective response or stable stable disease >6 months on TKI) leads to the inefficiency of the treatment(23). In more than 60% of patients who progressed with first and second generation TKI, the mechanism of resistance is an acquired substitution (threonine amino acid replacing methionine amino acid at 790 GateKeeper EGFR in exon 20 or T790M)(24).
Based on the data from the AURA 2 phase II study and the AURA extension cohort, T790M-positive tumors are responsive to treatment with the third generation of TKI osimertinib(25). However, secondary mutations have also been described as a mechanism of resistance to osimertinib.
There is some evidence suggesting the use of EGFR mutation first-line osminerinib on the basis of real evidence of better overall survival compared with second-line osimertenib after the resistance acquired in the first generation of TKI.
Currently, overall survival data from the FLAURA study is too immature to be interpretable, especially considering the likely effects of confronting the transition from the erlotinib/gefitinib arm to osimertinib.
In addition to the T790M, the emergence of other resistance mechanisms, including MET activation, HER2 amplification, Pi3 kinase and BRAF mutations, and the transformation into small cell lung cancer support rebirth to clinical progression to determine molecular/morphological changes and to personalize therapy consequence(26).
The treatment of the acquired resistance to TKI is based on the mechanisms of this resistance. The treatment of resistance acquired by TKI involves administering another targeted therapy to genetic changes that have led to resistance or, when these do not exist, to chemotherapy.
In the last decades – and especially in the last 10 years – remarkable progress has been made by using new advances in technology. A small number of early phase clinical trials with novel agents targeting both oncogenic and non-oncogenic signaling pathways have provided a wealth of biological information. Myriad early-phase clinical trials with novel agents targeting oncogene and non-oncogene addicted signaling pathways have provided a wealth of biologic information. With the availability of prospective pretreatment and post-treatment tumor biopsies, gene expression profiling in combination with high-throughput DNA sequencing for detection of genetic defects, proteomics (body fluids), and imaging (FDG-PET, DCE-MRI), early-phase trials are expected to provide biologic insights into response and resistance to therapy(27).
These studies have highlighted and continue to highlight the complexity of human tumor biology and the enormity of treatments at hand in order to achieve a curative treatment for the most common types of cancer.
Our understanding of the cellular and molecular mechanisms of cancer has allowed the development of adequate approaches to the treatment of cancer and this approaches is called “personalized medicine”. In this respect, targeted therapy was also included. This therapy addressed to the molecular abnormalities which should be detected by preliminary tests. The main issue of targeted therapy is to overcome drug resistance. It is also to be provided that more factors regulating and controlling the expression of the targeted drug resistance genes will be discovered in the future. We consider that more complex predictive methods are required in order to improve the response rates to targeted therapy.
Conflict of interests: The author declares no conflict of interests.