Drug Targets for Lung Cancer

Drug Targets for Lung Cancer

Drug targets for lung cancer: pharmacology information

Drug targets for lung cancer: bioreagents

Drug Targets EGFR for Lung Cancer with Approved Drugs

Drug targets Cancer drugs Company
EGFR Gefitinib AstraZeneca and Teva
EGFR Erlotinib Genentech and OSI Pharmaceuticals and elsewhere by Roche
EGFR Afatinib Dimaleate Boehringer Ingelheim
EGFR Icotinib Beta Pharma
EGFR Necitumumab Eli Lilly and Company
EGFR Osimertinib Tagrisso

Upon binding of a specific ligand (eg. epidermal growth factor), the normally functioning EGFR undergoes conformational change and phosphorylation of the intracellular domain occurs, leading to downstream signal transduction by various pathways. These include the Raf1-extracellular signal-regulated kinase, PI3K/Akt, and signal transducer and activator of transcription (STAT) factors. Depending on the pathway, the end result is cell proliferation or cell maintenance by inhibition of apoptosis. In non-small cell lung cancer, overexpression of EGFR or mutations in intracellular EGFR have been observed in 43-89% of cases, which can result in constitutive activation of signal transduction pathways, leading to cell proliferation or anti-apoptosis. So EGFR can be a good target in lung cancer targeted therapy(Ref: Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. Journal of Thoracic Disease. 2010;2(1):48-51.)

Drug Targets ALK for Lung Cancer with Approved Drugs

Drug targets Cancer drugs Company
ALK Crizotinib Pfizer
ALK Ceritinib Novartis Pharmaceuticals Corporation
ALK Alectinib Chugai Pharmaceutical

The fusion of the ALK gene with echinoderm microtubule-associated protein-like 4 (EML4) has been detected in 6.7% (5/75) of Japanese non-small cell lung cancers (NSCLC). ALK and EML4 are both located in the short arm of chromosome 2 separated by 12 megabases and are oriented in opposite 5′ to 3′ directions. Two different variants of EML4- ALK fusion gene have been characterized both involving exons 20-29 of ALK fused to exon 1-13 (variant 1) or 1–20 (variant 2) of EML4. Both variants of the EML4-ALK fusion gene were transforming in 3T3 cells and in Ba/F3 models. In these fusion proteins, the N-terminal portion is responsible for protein oligomerization, which leads to constitutive activation of ALK kinase, and results in aberrant activation of downstream signalling targets including Akt, STAT3, and extracellular regulated kinase 1/2 (ERK1/2). Inhibitors of ALK kinase have been developed and examined in preclinical models. Proof of concept studies using shRNA knockdown of ALK in NPM-ALK containing models led to growth inhibition and apoptosis and suggested that ALK inhibition may be a potentially effective therapeutic strategy. (Ref: Koivunen J P, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer[J]. Clinical cancer research, 2008, 14(13): 4275-4283.)

Drug Targets VEGF/VEGFR for Lung Cancer with Approved Drugs

Drug targets Cancer drugs Company
VEGF-A Bevacizumab Roche
VEGF-A Endostatin Simcere pharmaceutical
VEGFR2 Ramucirumab ImClone Systems Inc.

VEGF and VEGF-B are commonly expressed in Non-small cell lung cancer (usually at higher levels in adenocarcinoma than in squamous NSCLC), and have established roles in tumor cell proliferation, metastasis, and angiogenesis. VEGF activation of VEGFR-1, VEGFR-2, and downstream signaling pathways (eg, phosphoinositide 3 kinase [PI3K], phospholipase C-γ, and v-src sarcoma viral oncogene homolog [src]) is a well established initial step in promoting angiogenesis. Activation of these receptors triggers downstream signaling by the mitogen-activated protein kinase (MAPK) pathway, among others. (Ref: Piperdi B, Merla A, Perez-Soler R. Targeting Angiogenesis in Squamous Non-small Cell Lung Cancer. Drugs. 2014;74(4):403-413.).

Drug Targets PDGF/PDGFR for Lung Cancer with Approved Drugs

Drug targets Cancer drugs Company
PDGFR-αPDGFR-β Nintedanib Boehringer Ingelheim

PDGFs are a family of 5 ligands (ie, PDGF-AA, -AB, -BB, -CC, and -DD) that bind and activate 2 tyrosine kinase receptors, PDGF-α and –β, with varying affinities. Activation of these receptors triggers signaling through various downstream pathways. In NSCLC, PDGF has been shown to be an autocrine regulator of VEGF expression, suggesting a role for PDGF in tumor progression via angiogenesis. In addition, according to a single-center study of surgical sections of NSCLC tumors and cell lines, PDGF influences tumor size and patient prognosis more so than VEGF. (Ref: Piperdi B, Merla A, Perez-Soler R. Targeting Angiogenesis in Squamous Non-small Cell Lung Cancer. Drugs. 2014;74(4):403-413.)

Drug Targets PD1/PD-L1 for Lung Cancer with Approved Drugs

Drug targets Cancer drugs Company
PD-1 Pembrolizumab Merck
PD-1 Nivolumab Bristol-Myers Squibb
PD-L1 Atezolizumab Genentech/Roche

PD-L1 overexpression on mouse mastocytoma models inhibited tumor-directed T cell cytotoxicity in vitro and furthermore promoted apoptosis of tumor-specific T cells and immune evasion, these effects were neutralized by antibody-mediated blockade of PD-L1. Moreover in several experiments, blockade of PD-L1 could promote immune-mediated destruction of tumors which expressed PD-L1. PD-1 overexpression on CD8+ T cells in Non-small cell lung cancer suggests a reduced production of various cytokines and T cell proliferation. Abnormal expression PD-L1 has been identified in a range of 19% to 100% of Non-small cell lung cancer tumor cases, and associated with poor prognosis. On the other hand, PD-L1+ cells are remarkably increased comparing with adjacent lung parenchyma, and PD-L1 expression on Non-small cell lung cancer cells also correlates with poor prognosis and shortened OS. Hence it can be indicated that blockade of PD-1 interactions allows the tumor-specific T cell to unleash its full armamentarium of effector function on the Non-small cell lung cancer cells. (Ref: Ji M, Liu Y, Li Q, et al. PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation. Journal of Translational Medicine. 2015;13:5.)

Drug Targets ROS1 for Lung Cancer with Approved Drugs

Drug targets Cancer drugs Company
ROS1 Crizotinib Pfizer

ROS1 is an orphan receptor tyrosine kinase encoded by the ROS1 gene that is vulnerable to intrachromosomal or interchromosomal rearrangements, resulting in transforming gene fusions that occur in tumor types including Non-small cell lung cancer. ROS1 gene rearrangements were first recognized in Non-small cell lung cancer in 2007 and have since been described in 1% to 2% of patients with Non-small cell lung cancer. At least 11 fusion partners have been identified in Non-small cell lung cancer, including CD74-ROS1, SDC4-ROS1, EZR-ROS1, and SLC34A2-ROS1, all of which maintain a constant breakpoint in ROS1, preserving the kinase domain and resulting in aberrant ROS1 expression with constitutive kinase activity. These rearrangements may be detected in clinical samples by a variety of techniques, including fluorescent in situ hybridization, immunohistochemistry, reverse-transcriptase polymerase chain reaction, and next-generation sequencing. Patients with ROS1-rearranged Non-small cell lung cancer share many clinical features in common with ALK-rearranged Non-small cell lung cancer in that they are typically younger, are never-smokers, and have tumors with adenocarcinoma histology. ROS1 and ALK share substantial sequence homology in their kinase domains. Crizotinib, also a potent inhibitor of the ROS1 kinase, has activity in ROS1-rearranged non-small cell lung cancer models, providing a rationale for its evaluation in patients with ROS1 rearranged Non-small cell lung cancer (Ref: Solomon B. Validating ROS1 rearrangements as a therapeutic target in non–small-cell lung cancer[J]. 2015.).

Drug Targets HER2 for Lung Cancer with Approved Drugs

Drug targets Cancer drugs Company
HER2 Afatinib Boehringer Ingelheim

Oncogenic driver mutations identified in non-small cell lung cancer (NSCLC) have triggered the development of drugs capable of interfering in intracellular signaling pathways involved in tumorigenesis. Tyrosine kinase inhibitors, such as erlotinib or gefitinib, have demonstrated promising results in patients with advanced non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Human epidermal growth factor 2 (HER2/ERBB2/neu) is a member of the ERBB family of tyrosine kinase receptors, and is activated by homodimerization or heterodimerization with other ERBB receptors. Deregulation of HER2 gene, by overexpression and/or gene amplification has been proved important in breast and gastric cancer, in which overexpression of HER2 confers greater response to specific anti-HER2 treatment, including trastuzumab. In lung carcinogenesis, HER2 mutations are thought to be more clinically relevant than overexpression or gene amplification. HER2 mutations in non-small cell lung cancer (NSCLC), described exclusively in adenocarcinoma histology, are present in approximately 4% of this subset of lung cancer patients, suggesting that thousands of patients per year may possibly benefit from targeted therapy. (Ref: Garrido-Castro AC, Felip E. HER2 driven non-small cell lung cancer (NSCLC): potential therapeutic approaches. Translational Lung Cancer Research. 2013;2(2):122-127.).

Drug targets for Lung Cancer: Related Information