Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM

Song, Kwon‐Ho; Niederst, Matthew J.; Lochmann, Timothy L.; Hata, Aaron N.; Kitai, Hidenori; Ham, Jungoh; Floros, Konstantinos V.; Hicks, Mark; Hu, Haichuan; Mulvey, Hillary E.; Drier, Yotam; Heisey, Daniel A.R.; Hughes, Mark; Patel, Neha U.; Lockerman, Elizabeth L.; Garcia, Angel R.; Gillepsie, Shawn; Archibald, Hannah L.; Gomez‐Caraballo, María; Nulton, Tara J.; Windle, Brad E.; Piotrowska, Zofia; Sahingur, Sinem E.; Taylor, Shirley M.; Dozmorov, Mikhail G.; Sequist, Lecia V.; Bernstein, B; Ebi, Hiromichi; Engelman, Jeffrey A.; Faber, Anthony C.

doi:10.1158/1078-0432.ccr-17-1577

Cited by 76 publications

(64 citation statements)

References 60 publications

(106 reference statements)

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“…Many of them, as discussed earlier, suggested that transition toward mesenchymal phenotype co-occurs with a kinase switch. However, in some cases, bypass activation was not identified, suggesting that EMT itself might be responsible for the development of therapyrefractory disease (Lee A. F. et al, 2017;Song et al, 2018;Yochum et al, 2019).…”

Section: Emt In the Absence Of Bypass Activationmentioning

confidence: 99%

“…Additionally, expression of pro-mesenchymal factor TWIST in EGFR-mutant NSCLC has been linked to induction of EMT and acquired resistance to EGFR TKIs. Some studies suggest that TWIST can inhibit transcriptional activation of pro-apoptotic protein BIM either by directly binding to its promoter, or by inducing ZEB1, which then acts as a repressor of BIM transcription (Song et al, 2018;Yochum et al, 2019). Therefore, BH3 mimetics, a class of drugs that target BCL family of proteins to promote apoptosis, may be beneficial for treating EMTassociated EGFR TKI resistance.…”

Section: Emt In the Absence Of Bypass Activationmentioning

confidence: 99%

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Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

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Section: Emt In the Absence Of Bypass Activationmentioning

confidence: 99%

Section: Emt In the Absence Of Bypass Activationmentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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“…Bim is the only BH3 protein controlling cell death by binding anti-apoptotic proteins and activation of Bax and Bak. Down-regulation of Bim protein expression induces an anti-cancer drug resistance and inhibits cell death in cancers [42][43][44]. Therefore, up-regulation of Bim protein expression is targeted to induce cancer cell death.…”

Section: Discussionmentioning

confidence: 99%

Hispidulin Enhances TRAIL-Mediated Apoptosis via CaMKKβ/AMPK/USP51 Axis-Mediated Bim Stabilization

Woo

Seo

Kim

et al. 2019

Cancers

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Hispidulin, a natural compound present in herbs, has anti-cancer effects. Here, we investigated whether hispidulin sensitizes human carcinoma cells to apoptosis induced by TRAIL. Sub-lethal dosages of TRAIL alone and hispidulin alone does not increase apoptosis, but hispidulin increases sensitivity to TRAIL, resulting in induction of apoptosis in hispidulin plus TRAIL-treated cancer cells. In addition, combined treatment with hispidulin and TRAIL also reduced tumor growth and increased apoptosis in xenograft models. However, hispidulin did not alter cell viability in human renal normal mesangial cells and human skin fibroblast. Hispidulin markedly increased the BH3-only proteins Bim at the post-translational levels. Depletion of Bim with siRNA significantly blocked hispidulin plus TRAIL-induced apoptosis. Furthermore, we found that activation of AMPK by hispidulin has a crucial role in Bim proteins stability through up-regulation of USP51 expression. Our findings suggest that USP51-dependent stabilization of Bim by AMPK activation plays a critical role in hispidulin-mediated sensitization of cancer cells to apoptosis induced by TRAIL.

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“…The transcriptional state change known as epithelial-tomesenchymal transition (EMT) is another important resistance mechanism to targeted therapies including EGFR inhibitors (65). The precise mechanisms underlying EMT are still being investigated, but suppression of BIM and upregulation of AXL, SRC, TGFb, and IFG1R have all been associated with EMT and resistance to targeted therapy (65)(66)(67)(68). Of note small molecule inhibitors of the kinase AXL have been shown to re-sensitize resistant mesenchymal cells to EFGR inhibitors, suggesting AXL as a potential therapeutic target in resistant NSCLC (67).…”

Section: Mechanisms Of Resistance In Alternate Bypass Pathwaysmentioning

confidence: 99%

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

et al. 2019

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EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a thirdgeneration tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.

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Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM

Cited by 76 publications

References 60 publications

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Hispidulin Enhances TRAIL-Mediated Apoptosis via CaMKKβ/AMPK/USP51 Axis-Mediated Bim Stabilization

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

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