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    • Drug resistance development often involves structurally un r

    2023-03-16

    Drug resistance development often involves structurally un-related drugs and, specifically both conventional and targeted agents. IGROV-1/Pt1 MRS 2578 receptor are characterized by resistance to cisplatin and reduced sensitivity to inhibitors of EGF-R and MEK, the up-stream activator of ERK1/2, associated with EGF-R up-regulation [28]. Here we show that, in contrast to the parental IGROV-1 cell line, the platinum-resistant cells present also a constitutive activation of ErbB3. Under our experimental conditions, Axl silencing did not produce any change of sensitivity of IGROV-1/Pt1 cells to the MEK inhibitor CI-1040, whereas it tended to decrease sensitivity to gefitinib. Notably, ErbB3 is known to contribute to acquired resistance to gefitinib [29]. Axl silencing did not result in modulation of sensitivity to cisplatin or taxol. Thus, molecular targeting of Axl in these cells does not allow overcoming resistance to drugs employed in the first line treatment of ovarian carcinoma. This finding is consistent with the available literature reporting only indirect relationships between Axl and cisplatin resistance. In fact, decreased Axl levels were found in cisplatin resistant lung cancer cells after exposure to epigallocatechin gallate, which exerts an antiproliferative effect also in cisplatin-resistant cells [30]. Moreover, in an acute leukemia myeloid cell line, Axl is induced by cisplatin exposure [31]. In the same study, Axl over-expression induced a mild change in sensitivity to cisplatin (around 2-fold change of IC50 level) when cells are pre-treated with Axl ligand before cisplatin exposure. In addition, although it has been observed that pharmacological Axl inhibition resulted in sensitization to taxanes [32], molecular inhibition of Axl did not produced a change in sensitivity to taxol in our study. This observation suggests that some off-target effects of Axl inhibitors may cooperate to alter chemosensitivity of tumor cells. An interesting finding of the present study was the possibility to obtain a synergistic interaction between cisplatin and the ErbB family inhibitor AZD8931. In this regard, targeting of ErbB3 receptor has been proposed a strategy to overcome drug resistance in cancer treatment [33]. The fact that sensitization of drug-resistant cells may require the concomitant inhibition of multiple survival pathways, may have clinical implications for the treatment of ovarian carcinomas refractory to cisplatin. In fact, molecular targeted therapy administered alone or in combination with platinum-based drugs has shown promising results [34]. Concerning the role of Axl in ovarian carcinoma aggressiveness, useful information can be obtained by the results regarding the oxaliplatin-resistant cell line. Indeed, IGROV-1/OHP cells, despite increased Axl levels with respect to parental cells do not display increased migratory and invasive ability. It is therefore possible that a threshold expression level of Axl needs to be achieved to acquire a pro-migratory/invasive phenotype. Overall, our results support a contribution of Axl to ovarian carcinoma aggressiveness and exclude a direct relationship to cisplatin resistance. Moreover, the concomitant inhibition of multiple factors appears to be required to sensitize drug-resistant cells to cisplatin.
    Acknowledgements We thank Giacomo Cossa for gene expression analysis. This work was supported by a grant to PP from the Associazione Italiana per la Ricerca sul Cancro (AIRC-IG 15333).
    Introduction Epidermal growth factor receptor (EGFR) signaling was defined by Weinstein [1] in 2002 as an “oncogene addiction” pathway that has crucial importance to tumor cell survival in lung adenocarcinoma. Inhibitors targeting EGFR signaling (tyrosine kinase inhibitors [TKIs] and monoclonal EGFR antibodies) have been clinically evaluated and are effective therapeutic strategies in non–small cell lung cancer (NSCLC). However, resistance to such drugs is unfortunately caused by intrinsic resistance, which is defined as the failure to respond to treatment, or by acquired resistance, which denotes disease progression after an initial response [2], [3]. Thus, the identification of relevant resistance mechanisms is essential to developing a strategy to overcome resistance and prolong the efficacy of EGFR-targeted therapies.