HER2-directed therapies, such as trastuzumab and lapatinib, are important treatments for breast cancer. However, some tumors do not respond or develop resistance to these agents. We isolated and characterized multiple lapatinib-resistant, HER2-positive, estrogen receptor (ER)-positive breast cancer clones derived from lapatinib-sensitive BT474 cells by chronic exposure to lapatinib. We show overexpression of AXL as a novel mechanism of acquired resistance to HER2-targeted agents in these models. GSK1363089 ( foretinib), a multikinase inhibitor of AXL, MET, and vascular endothelial growth factor receptor currently in phase II clinical trials, restores lapatinib and trastuzumab sensitivity in these resistant cells that exhibit increased AXL expression. Furthermore, small interfering RNA to AXL, estrogen deprivation, or fulvestrant, an ER antagonist, decreases AXL expression and restores sensitivity to lapatinib in these cells. Taken together, these data provide scientific evidence to assess the expression of AXL in HER2-positive, ER-positive patients who have progressed on either lapatinib or trastuzumab and to test the combination of HER2-targeted agents and GSK1363089 in the clinic. [Cancer Res 2009;69(17):6871-8]

Recent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAF V600E and the YUSIT1 BRAF V600K melanoma cell lines. These clones also showed reduced sensitivity to the allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor GSK1120212 (trametinib).

By regulating activities and expression levels of key signaling molecules, estrogens control mechanisms that are responsible for crucial cellular functions. Ligand binding to estrogen receptor (ER) leads to conformational changes that regulate the receptor activity, its interaction with other proteins and DNA. In the cytoplasm, receptor interactions with kinases and scaffolding molecules regulate cell signaling cascades (extranuclear/nongenomic action). In the nucleus, estrogens control a repertoire of coregulators and other auxiliary proteins that are associated with ER, which in turn determines the nature of regulated genes and level of their expression (genomic action). The combination of genomic and nongenomic actions of estrogens ultimately confers the cell-type and tissue-type selectivity. Recent studies have revealed some important new insights into the molecular mechanisms underlying ER action, which may help to explain the functional basis of existing selective ER modulators (SERMs) and provide evidence into how ER might be selectively targeted to achieve specific therapeutic goals. In this review, we will summarize some new molecular details that relate to estrogen signaling. We will also discuss some new strategies that may potentially lead to the development of functionally selective ER modulators that can separate between the beneficial, prodifferentiative effects in bone, the cardiovascular system and the CNS as well as the ''detrimental,'' proliferative effects in reproductive tissues and organs.

Integration of viral DNA into host DNA is an essential step in the replication cycle of retroviruses and retrotransposons (4, 13, 26). The first two steps in this process, viral DNA processing and joining, are catalyzed by the retroviral protein integrase and require specific sequences at the ends of the viral DNA. In the first step, nucleotides (usually two) are removed from the 3Ј ends of the viral DNA, and in the second step, these newly created ends are joined to staggered phosphates in the complementary strands of the host cell DNA, creating an integration intermediate with gaps in the DNA sequence. Complete, stable integration of the viral DNA depends on repair of these gaps: filling in the missing nucleotides, removing the short flap on the 5Ј ends of the viral DNA, ligation to the newly synthesized 3Ј end of host DNA and, likely, reconstitution of appropriate chromatin structure and composition, all by mechanisms not yet fully understood.At each step, the retroviral DNA integration process may be assisted by host cellular proteins, including those that participate in DNA repair. Mechanistically, retroviral DNA integration resembles RAG1/2-mediated V(D)J recombination, the process by which immunoglobulin genes are assembled (5). Successful completion of V(D)J recombination depends on proteins that make up the nonhomologous end joining (NHEJ)