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  • br Resistance to targeted therapy The

    2022-08-04


    Resistance to targeted therapy The idea of treating HER2 mutant tumors with specific therapies is relatively new and, as a consequence, little is known about the potential mechanisms of resistance to anti-HER2 agents in this setting. Primary resistance may be mediated by the presence of on-target mutations that hamper the binding of first generation TKIs such as Lapatinib. Studies have shown that three point mutations (L755S, L755P and T798 M) confer primary as well as acquired resistance to this agent (Bose et al., 2013; Kancha et al., 2011). Acquired resistance can also be mediated by the emergence of de novo mutations in HER2. Hanker et al. reported a case in which the emergence of the gatekeeper HER2 T798I was identified in the cfDNA of a HER2 L869R-mutant breast cancer patient who initially responded and then progressed to Neratinib. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 T798I reduces Neratinib binding by generating steric hindrance. Interestingly, while this mutation induced Neratinib resistance, Afatinib and the Osimertinib metabolite AZ5104 were still able to suppress cell growth in transduced preclinical models (Hanker et al., 2017). In addition to on-target mechanisms, it has been described that TP53, PIK3CA and K-RAS mutations may contribute to intrinsic resistance to anti-HER2 therapy in HER2 overexpressing or EGFR mutated tumors (Black et al., 2015; Canale et al., 2017; Linardou et al., 2008; Ma et al., 2017). Cyclin E gene amplification also has been reported as mechanism of resistance to Trastuzumab in several cancer models (Cocco et al., 2016; Scaltriti et al., 2011). These genomic alterations may therefore also contribute to confer resistance to anti-HER2 therapies in the context of HER2 mutant tumors. As mentioned before, TP53, PIK3CA and CCNE are among the most altered genes in HER2 mutated Temafloxacin hydrochloride cancers, thus potentially explaining why these tumors are refractory to anti HER2 therapies. Moreover, among the 66 total patients of the SUMMIT trial that did not respond to Neratinib monotherapy, HER3 mutations were found in 14% of their tumors. Although additional studies are needed Temafloxacin hydrochloride to evaluate whether these mutations can confer resistance to Neratinib, it has recently been demonstrated that breast cancer cell lines harboring HER3 mutations (F94 L, G284R, D297Y, T355I, and E1261A) have enhanced HER2-HER3 heterodimerization that induces a gain-of-function phenotype and results in Lapatinib resistance (Mishra et al., 2018). Furthermore, it has been recently demonstrated that the FDA-approved pan-ERBB inhibitors Afatinib and Neratinib effectively reduced the expression of mutant K-RAS proteins in several tumor types (Booth et al., 2018; Booth et al., 2019; Moll et al., 2018), thus supporting the use of these agents to treat K-RAS mutated cancers.
    Conclusions Despite their low frequency, activating HER2 mutations have recently emerged as novel therapeutic targets for a variety of human tumors. Although anti-HER2 therapies have shown promising clinical results in a subset of HER2-mutated breast, lung and cervical cancer patients, the same therapies were largely inefficacious in other tumor types such as bladder and colorectal cancers. Whether the lack of responses is related to concurrent presence of genomic alterations that can obliterate the dependency to HER2-mutations remains to be elucidated, but the available data from basket trials suggest that ad hoc registrational clinical studies may be successfully designed for specific histologies. In this context, the use of novel emerging anti-HER2 agents or combinatorial treatments may represent meaningful advancements for the treatment of HER2 mutated cancer patients.
    Conflict of interest statement
    Acknowledgments
    Introduction Intestinal-type sinonasal adenocarcinoma (ITAC) is an aggressive neoplasm, morphologically and immunophenotypically similar to primary colonic adenocarcinoma [1]. It accounts for about 18% of sinonasal cavities adenocarcinomas, with an incidence of less than 1 case per 100,000 individuals per year, and occurs primarily in males [2,3]. The majority of ITACs (88%) has been associated with occupational exposure to wood and leather dust, with a hundredfold higher risk in exposed versus non-exposed population [[2], [3], [4]]. Local spread of the disease and recurrences are responsible for clinical outcome, which has not significantly changed over the last decades [5].