Acquired Resistance to Erlotinib in A-431 Epidermoid Cancer Cells Requires Down-regulation of MMAC1/PTEN and Up-regulation of Phosphorylated Akt

Yamasaki, Fumiyuki; Johansen, Mary; Zhang, Dongwei; Krishnamurthy, Savitri; Felix, Edward; Bartholomeusz, Chandra; Aguilar, Richard J.; Kurisu, Kaoru; Mills, Gordon B.; Hortobágyi, Gabriel N.; Ueno, Naoto T.

doi:10.1158/0008-5472.can-06-3020

Cited by 101 publications

(109 citation statements)

References 45 publications

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“…However, the efficacy of erlotinib or lapatinib as a monotherapy is limited by the development of therapeutic resistance in NSCLC or breast cancers, respectively (33)(34)(35)(36). Thus, strategies are needed to overcome such resistance.…”

Section: Discussionmentioning

confidence: 99%

MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted DrugsIn vitroandIn vivo

Hirai

Sootome

Nakatsuru

et al. 2010

Molecular Cancer Therapeutics

824

645

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The serine/threonine kinase Akt lies at a critical signaling node downstream of phosphatidylinositol-3-kinase and is important in promoting cell survival and inhibiting apoptosis. An Akt inhibitor may be particularly useful for cancers in which increased Akt signaling is associated with reduced sensitivity to cytotoxic agents or receptor tyrosine kinase inhibitors. We evaluated the effect of a novel allosteric Akt inhibitor, MK-2206, in combination with several anticancer agents. In vitro, MK-2206 synergistically inhibited cell proliferation of human cancer cell lines in combination with molecular targeted agents such as erlotinib (an epidermal growth factor receptor inhibitor) or lapatinib (a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor). Complementary inhibition of erlotinib-insensitive Akt phosphorylation by MK-2206 was one mechanism of synergism, and a synergistic effect was found even in erlotinib-insensitive cell lines. MK-2206 also showed synergistic responses in combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin, camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206 suppressed the Akt phosphorylation that is induced by carboplatin and gemcitabine. In vivo, MK-2206 in combination with these agents exerted significantly more potent tumor inhibitory activities than each agent in the monotherapy setting. These findings suggest that Akt inhibition may augment the efficacy of existing cancer therapeutics; thus, MK-2206 is a promising agent to treat cancer patients who receive these cytotoxic and/or molecular targeted agents. Mol Cancer Ther; 9(7); 1956-67.

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Section: Discussionmentioning

confidence: 99%

MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted DrugsIn vitroandIn vivo

Hirai

Sootome

Nakatsuru

et al. 2010

Molecular Cancer Therapeutics

824

645

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“…Loss of PTEN is involved in the development of EGFR inhibitor resistance in certain tumor cell lines (23,24) and in patients with glioblastoma (25). The underlying mechanisms may include promoter hypermethylation, post-translational modifications or the alternative splicing of the pre-mRNA (26).…”

Section: Discussionmentioning

confidence: 99%

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

Zhai¹,

Zhang²,

Kang

et al. 2017

Oncology Letters

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Abstract. The clinical resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been linked to EGFR T790M resistance mutations or MET amplifications. Additional mechanisms underlying EGFR-TKI drug resistance remain unclear. The present study demonstrated that icotinib significantly inhibited the proliferation and increased the apoptosis rate of HCC827 cells; the cellular mRNA and protein expression levels of phosphatase and tensin homolog (PTEN) were also significantly downregulated. To investigate the effect of PTEN expression levels on the sensitivity of HCC827 cells to icotinib, PTEN expression was silenced using a PTEN-specific small interfering RNA. The current study identified that the downregulation of PTEN expression levels may promote cellular proliferation in addition to decreasing the apoptosis of HCC827 cells, and may reduce the sensitivity of HCC827 cells to icotinib. These results suggested that reduced PTEN expression levels were associated with the decreased sensitivity of HCC827 cells to icotinib. Furthermore, PTEN expression levels may be a useful marker for predicting icotinib resistance and elucidating the resistance mechanisms underlying EGFR-mutated NSCLC.

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“…These effects are mainly mediated by activation of downstream pathways, including the two major pathways-phosphatidylinositol-3 kinase (PI3K)-AKT pathway and mitogen-activated protein kinase ((MAPK) pathway (Mendelsohn and Baselga, 2000). Preclinical studies showed that continued activation of downstream signaling pathways, especially PI3k/AKT, is sufficient to confer resistance to EGFR-TKI by bypassing the EGFR blocking (Yamasaki et al, 2007). Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is located on chromosome 10q23.3 and encodes a 403 amino acid dual-specificity lipid and protein phosphatese, which functions as a tumor suppressor in many tumors (Tamura et al, 1998;Sulis and Parsons, 2003).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-214 Regulates the Acquired Resistance to Gefitinib via the PTEN/AKT Pathway in EGFR-mutant Cell Lines

Wang¹,

Wang²,

Xia³

et al. 2012

Asian Pacific Journal of Cancer Prevention

104

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Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors ((EGFR-TKIs)-namely gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. Despite the fact that this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as T790M or amplification of the MET proto-oncogene, there are other mechanisms which need to be explored. MicroRNAs (miRs) are a class of small non-coding RNAs that play pivotal roles in tumorigenesis, tumor progression and chemo-resistance. In this study, we firstly successfully established a gefitinib resistant cell line-HCC827/GR, by exposing normal HCC827 cells (an NSCLC cell line with a 746E-750A in-frame deletion of EGFR gene) to increasing concentrations of gefitinib. Then, we found that miR-214 was significantly up-regulated in HCC827/ GR. We also showed that miR-214 and PTEN were inversely expressed in HCC827/GR. Knockdown of miR-214 altered the expression of PTEN and p-AKT and re-sensitized HCC827/GR to gefitinib. Taken together, miR-214 may regulate the acquired resistance to gefitinib in HCC827 via PTEN/AKT signaling pathway. Suppression of miR-214 may thus reverse the acquired resistance to EGFR-TKIs therapy.

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Acquired Resistance to Erlotinib in A-431 Epidermoid Cancer Cells Requires Down-regulation of MMAC1/PTEN and Up-regulation of Phosphorylated Akt

Cited by 101 publications

References 45 publications

MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted DrugsIn vitroandIn vivo

MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted DrugsIn vitroandIn vivo

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

MicroRNA-214 Regulates the Acquired Resistance to Gefitinib via the PTEN/AKT Pathway in EGFR-mutant Cell Lines

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