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

Shanthi Kanthala; Sandeep Pallerla; Seetharama Jois

Disclosures

Future Oncol. 2015;11(5):865-878. 

In This Article

EGFRs in NSCLC

EGFR

EGFR overexpression in premalignant and malignant lung tissues is varied showing overexpression in the range of 40–80% of NSCLC patients.[16] In 2004, before EGFR mutation was known to be a predictive biomarker, it was assumed that certain patient populations benefited more from EGFR TKIs, namely, those with lung ADCs, those of Asian ethnicity, females, and never smokers. It is now known that the enhanced efficacy in these populations is due to the EGFR mutations in their tumors. Also, these mutations are found almost exclusively in ADCs of the lung. There is, however, no clinical characteristic that can be used instead of EGFR mutation testing to detect lung cancers. Recently, it has been observed that the role of EGFR signaling is significant in glycolysis, the pentose phosphate pathway and pyrimidine biosynthesis in EGFR-mutated lung cancer.[17]

HER2

ERBref-2/HER2/neu is overexpressed in NSCLC and is considered to be a significant and independent prognostic factor in lung cancer. The exact percentage of HER2 overexpression in NSCLC is not clear as reported literature suggests overexpression rates ranging from 4 to 27%.[18] This variation is not due to lung cancer cells, but seems to arise from the methods used to assess HER2 overexpression. The frequency of HER2 positivity depends on the types of tumor tissues, in other words, whether they are ADCs (17–42%), large-cell carcinomas (2–40%) or squamous carcinomas (0–5%). Some NSCLC patients with a chemoresistant phenotype may also show overexpression of HER2. During 2004–2005 clinical trials conducted on NSCLC patients by treating them with the HER2-targeted antibody trastuzumab[19] in addition to gemcitabine-cisplatin or docetaxel, the benefits of HER2-targeted treatment for lung cancer were not demonstrated. However, Capizzo et al.[20] have shown that patients with lung cancer who have HER2 mutation G776L respond to treatment with trastuzumab and paclitaxel therapy. This reinforces the fact that HER2-targeted therapy for HER2-overexpressed lung cancer depends on the method used for assessment of HER2 overexpression. Studies related to a dual kinase inhibitor afatinib (inhibits both EGFR and HER2 kinase activity) clearly demonstrate the importance of HER2 overexpression and mutation and targeted therapy for HER2-positive NSCLC.[21] Recent findings suggest that long-term HER2 overexpression could induce serious lung inflammation and some precancerous lesions by upregulating inflammatory factors such as TNF, IL-1 and IL-6.[22]De novo mutations in HER2 are present in 2–5% of NSCLC[23] and up to approximately 10% in ADCs with a phenotype similar to tumors with EGFR mutations. The majority (>95%) of these represent small insertions in exon 20, which cause a duplication of the amino acids YVMA that results in constitutive activation of HER2.[24] Based on cumulative experience to date, HER2 mutations are thought to be more clinically relevant in NSCLC than overexpression of HER2 protein or HER2 gene amplification.[12] Studies regarding HER2 mutations suggest that they occurred in never smokers and, in particular, in the Asian population. Further studies are needed to answer some controversial results observed in HER2-positive NSCLC patients. There is an ongoing Phase II study of the use of the dual inhibitor neratinib in patients with NSCLC.[25]

Coexpression of EGFR & HER2

NSCLCs that overexpress both EGFR and HER2 demonstrate aggressive tumor cell growth. HER2 has been identified as the preferred binding partner of the other ERBB receptors, in particular, of EGFR with the formation of HER2/EGFR heterodimers with greater potential for signaling than EGFR homodimers. Some studies have demonstrated that NSCLCs that overexpress both EGFR and HER2 are more sensitive TKIs than a tumor with an increased expression of EGFR alone.[16] Recently, it has been shown that NSCLCs that overexpress both EGFR and HER2 proteins demonstrate aggressive tumor cell growth[16,26] and are associated with a significantly shortened overall survival rate.[27] It is known from a clinical trial that a correlation exists between the overall survival rate in NSCLC and coexpression of EGFR and HER2 than that in patients with tumors with high levels of EGFR or HER2 alone.[27] It is well known that heterodimerization of EGFR and transphosphorylation results in downstream signaling in pathways such as PI3K/Akt. This pathway is initiated by HER3, which lacks a kinase domain. However, HER2 is a major dimerization partner for EGFR and HER3. Since HER2 plays an important role in dimerization of receptors and phosphorylation and is important in driving the MAPK and PI3K/Akt pathways, targeting HER2 and inhibiting EGFR:HER2 and HER2:HER3 dimerization should have a significant impact on HER2-overexpressed lung cancer, in particular, NSCLC.

HER3

Recent evidence suggests that Erbref-3/HER3, one of the members of the EGFR receptor family, is upregulated in NSCLC and is involved in drug resistance through increased intracellular phosphorylation, which thereby activates PI3K/Akt signaling.[28] However, the HER3 kinase domain is only weakly active, and HER3 needs a dimerization partner for signaling. HER3 must be phosphorylated for signaling, and the most probable partner is HER2. Hence, studies related to HER3 are in progress at present.[29] The erbref-3/PI3K/Akt pathway is a major cause of treatment failure in cancer therapy because of its role in therapeutic resistance.[30] Attempts at treatments targeted to HER3 are concentrated particularly on EGFR TKI-resistant NSCLC.[29]

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