Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers.

The EGFR family is among the most investigated receptor protein-tyrosine kinase groups owing to its general role in signal transduction and in oncogenesis. This family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). The ErbB proteins function as homo and heterodimers. These receptors contain an extracellular domain that consists of four parts: domains I and III are leucine-rich segments that participate in growth factor binding (except for ErbB2) and domains II and IV contain multiple disulfide bonds. Moreover, domain II participates in both homo and heterodimer formation within the ErbB/HER family of proteins. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor-α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The extracellular domain is followed by a single transmembrane segment of about 25 amino acid residues and an intracellular portion of about 550 amino acid residues that contains (i) a short juxtamembrane segment, (ii) a protein kinase domain, and (iii) a carboxyterminal tail. ErbB2 lacks a known activating ligand and ErbB3 is kinase impaired. Surprisingly, the ErbB2-ErbB3 heterodimer complex is the most active dimer in the family. These receptors are implicated in the pathogenesis of a large proportion of lung and breast cancers, which rank first and second, respectively, in the incidence of all types of cancers (excluding skin) worldwide. On the order of 20% of non-small cell lung cancers bear activating mutations in EGFR. More than 90% of these patients have exon-19 deletions (746ELREA750) or the exon-21 L858R substitution. Gefitinib and erlotinib are orally effective type I reversible EGFR mutant inhibitors; type I inhibitors bind to an active enzyme conformation. Unfortunately, secondary resistance to these drugs occurs within about one year owing to a T790M gatekeeper mutation. Osimertinib is an irreversible type VI inhibitor that forms a covalent bond with C797 of EGFR and is FDA-approved for the treatment of patients with this mutation; type VI inhibitors generally form a covalent adduct with their target protein. Resistance also develops to this and related type VI inhibitory drugs owing to a C797S mutation; the serine residue is unable to react with the drugs to form a covalent bond. Approximately 20% of breast cancer patients exhibit ErbB2/HER2 gene amplification on chromosome 17q. One of the earliest targeted treatments in cancer involved the development of trastuzumab, a monoclonal antibody that interacts with the extracellular domain ErbB2/HER2 causing its down regulation. Surgery, radiation therapy, chemotherapy with cytotoxic drugs, and hormonal modulation are the mainstays in the treatment of breast cancer. Moreover, lapatinib and neratinib are FDA-approved small molecule ErbB2/HER2 antagonists used in the treatment of selected breast cancer patients. Of the approximate three dozen FDA-approved small molecule protein kinase inhibitors, five are type VI irreversible inhibitors and four of them including afatinib, osimertinib, dacomitinib, and neratinib are directed against the ErbB family of receptors (ibrutinib is the fifth and it targets Bruton tyrosine kinase). Avitinib, olmutinib, and pelitinib are additional type VI inhibitors in clinical trials for non-small cell lung cancer that target EGFR. Secondary resistance to both targeted and cytotoxic drugs is the norm, and devising and implementing strategies for minimizing or overcoming resistance is an important goal in cancer therapeutics.

Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases.

In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2+ BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM.

ErbB/HER protein-tyrosine kinases: Structures and small molecule inhibitors.

The epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). These receptors consist of an extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. The ErbB proteins function as homo and heterodimers. Growth factor binding to EGFR induces a large conformational change in the extracellular domain. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric dimer. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas. Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer and lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Moreover, monoclonal antibodies that target the extracellular domain of ErbB2 are used for the treatment of ErbB2-positive breast cancer and monoclonal antibodies that target ErbB1 and are used for the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them, and a current goal of research is to develop drugs that are effective against drug-resistant tumors.