![]() ![]() ![]() Thus, dual specificity inhibitors and combinatorial drug target approaches have been considered. However, a challenge in the development of PI3K inhibitors for antitumor therapies has been the redundancy within the PI3K/AKT/mTOR pathway and the ability of compensatory pathways to emerge, resulting in clinical resistance ( 21). Tumors containing PIK3CA mutations may reflect enhanced dependence on this prosurvival pathway and may predict enhanced sensitivity to PI3K pathway inhibition ( 22). #Aarons cube signal path driversActivating mutations in the PI3K p110α (PIK3CA) subunit are major drivers of many cancer types, including endometrial, ovarian, colorectal, bladder, lung, and breast cancer ( 21). ![]() Like CHK1, PI3K is also involved in HRR class1A PI3K isoforms act as a sensor of genomic instability by regulating the recruitment of the Nbs1 sensor protein to double-strand breaks, and by promoting Rad51 recombinase foci formation ( 19, 20). The PI3K/AKT/mTOR signaling pathway controls many biological processes, including cell growth, survival, proliferation, and metabolism, both under normal physiologic conditions, as well as in pathologies, such as cancer ( 18). The clinical benefit rate at 3 months across all tumor types was a modest 29%, suggesting that further evaluations in SCC should focus on combination therapy and/or biomarker-selected populations ( 6, 7). In an expansion cohort of patients with advanced squamous cell carcinoma (SCC) who received prexasertib at the recommended phase II dose (RP2D) of 105 mg/m 2, the most common treatment-related treatment-emergent adverse event (TEAE) was grade 4 neutropenia (71% ref. The primary toxicities of prexasertib monotherapy in the dose escalation phase were hematologic and included neutropenia, leukopenia, anemia, and thrombocytopenia ( 6). In the phase I study (NCT01115790), single-agent prexasertib therapy was the first CHK1 inhibitor to achieve antitumor objective responses in patients with advanced cancer ( 6). Prexasertib (LY2606368) is an adenosine-5′-triphosphate competitive inhibitor of CHK1, which induces DNA damage, including double-strand breaks and chromosomal fragmentation ( 17). Because of this, CHK1 inhibitors have been explored as an antitumor strategy, not only as amplifiers of DNA damage in combination with radiotherapy and genotoxic chemotherapy, but also as monotherapy or in combination with other targeted agents ( 6–16). Inhibition of CHK1, therefore, abrogates checkpoint control, prevents DNA damage repair, and can promote mitotic catastrophe and subsequent apoptosis ( 1). Importantly, CHK1 also regulates homologous recombination repair (HRR) and promotes resolution of replication stress by stabilization of active replication forks ( 3, 5). ![]() In response to DNA damage, CHK1 phosphorylates and inactivates the substrate CDC25C, resulting in CDK1/cyclin B1 inhibition and culminating in G 2–M-phase cell-cycle arrest ( 4). Checkpoint kinase 1 (CHK1) is a serine threonine kinase activated downstream of the checkpoint transducer, ataxia telangiectasia mutated and Rad3 related (ATR refs. Stringent checkpoint control is a key cellular mechanism that prevents propagation of genotoxic lesions by pausing cell-cycle progression to allow for DNA repair prior to entering mitosis or to promote apoptosis in cells with unrepaired lesions ( 1). ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |