Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.

Trastuzumab emtansine (T-DM1), an anti-erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years; male sex, 47%; performance status of 0 to 1, 80%; HER2 status IHC 3+, 33%; HER status IHC 2+/fluorescence in situ hybridization-positive, 20%; and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1-11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2-32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging; thus, additional molecular approaches are warranted.

Topoisomerases alter DNA topology and are vital for the maintenance of genomic integrity. Topoisomerases I and II are also targets for widely used antitumor agents. We demonstrated previously that in the human leukemia cell line, HL-60, resistance to topoisomerase (topo) II-targeting drugs such as etoposide is associated with site-specific hypophosphorylation of topo II␣. This effect can be mimicked in sensitive cells treated with the intracellular Ca 2؉ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N ,N -tetraacetic acid (BAPTA-AM). Here we identify Ser-1106 as a major phosphorylation site in the catalytic domain of topo II␣. This site lies within the consensus sequence for the acidotrophic kinases, casein kinase I and casein kinase II. Mutation of serine 1106 to alanine (S1106A) abrogates phosphorylation of phosphopeptides that were found to be hypophosphorylated in resistant HL-60 cells or sensitive cells treated with BAPTA-AM. Purified topo II␣ containing a S1106A substitution is 4-fold less active than wild type topo II␣ in decatenating kinetoplast DNA and also exhibits a 2-4-fold decrease in the level of etoposidestabilized DNA cleavable complex formation. Saccharomyces cerevisiae (JN394t2-4) cells expressing S1106A mutant topo II␣ protein are more resistant to the cytotoxic effects of etoposide or amsacrine. These results demonstrate that Ca 2؉ -regulated phosphorylation of Ser-1106 in the catalytic domain of topo II␣ modulates the enzymatic activity of this protein and sensitivity to topo II-targeting drugs.Topoisomerases alter DNA topology for the efficient processing of genetic material (1-3). These enzymes play a pivotal role in the maintenance of genomic integrity and are essential for many chromosomal functions including DNA replication and recombination, transcription, and chromosome segregation (1-3). Topoisomerases regulate various cellular processes by relaxing and untangling the intertwined strands of DNA. Two major categories of topoisomerases, type I and type II, have been characterized. The type II enzymes, which consist of two highly homologous isoforms in humans, topoisomerase (topo) 1 II␣ and topo II␤ with molecular masses of 170 and 180 kDa, respectively, catalyze the ATP-dependent transport of one intact DNA double helix through another by creating a transient double-stranded break (1).The essential nature of topo II␣ during cell proliferation and its ability to cleave DNA in a reversible manner makes topo II␣ an ideal target for agents that poison the enzyme (4, 5). In the presence of DNA-damaging topo II-targeting drugs, topo II is converted to a nuclease that irreversibly cleaves duplex DNA. The "poisoning" of the enzyme is via the trapping of the transient reaction intermediate, termed a cleavable complex, which is composed of topo II bound covalently to the 5Ј end of the cleaved DNA strands. This leads to DNA damage, apoptosis, genomic instability, and cell death. Several clinically effective cancer chemotherapeutic agents, daunorubicin, doxorubicin (DOX), amsacrine (m-AMSA), and eto...

Erlotinib should be considered for first-line treatment in this subset of Japanese patients, with close monitoring for ILD-like events.

DNA topoisomerase II enzymes regulate essential cellular processes by altering the topology of chromosomal DNA. These enzymes function by creating transient double-stranded breaks in the DNA molecule that allow the DNA strands to pass through each other and unwind or unknot tangled DNA. Because of the integral role of topoisomerases in regulating DNA metabolism, these enzymes are vital for cell survival. Several clinically active antitumor agents target these enzymes. Mammalian cells contain two topoisomerase II isozymes that are encoded by different genes: topoisomerase IIα and IIβ. Although, both isozymes are homologous and exhibit similar catalytic activity, they are differentially regulated and are involved in distinct biological functions. The topoisomerase IIα and topoisomerase IIβ enzymes are regulated by post-translational modifications, including sumoylation, ubiquitination and phosphorylation. These post-translational modifications influence the biologic and catalytic activity of the enzyme and affect sensitivity of cells to topoisomerase II-targeted drugs. In this review, we describe how the catalytic and biologic activity of the topoisomerase II enzyme is regulated and discuss the mechanisms by which chemotherapeutic agents that target these enzymes function. Given the potential importance of site-specific modifications, in particular phosphorylation, in regulating sensitivity to topoisomerase II-targeted drugs, we discuss the potential role of altered topoisomerase II phosphorylation in development of drug resistance, which is often a limiting factor in the treatment of cancer.