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16 pages, 3288 KiB

Open AccessArticle

Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer

by Katherine B. Sahin, Esha T. Shah, Genevieve P. Ferguson, Christopher Molloy, Priyakshi Kalita-de Croft, Sarah A. Hayes, Amanda Hudson, Emily Colvin, Hannah Kamitakahara, Rozelle Harvie, Csilla Hasovits, Tashbib Khan, Pascal H. G. Duijf, Viive M. Howell, Yaowu He, Emma Bolderson, John D. Hooper, Sunil R. Lakhani, Derek J. Richard, Kenneth J. O’Byrne and Mark N. Adams Show full author list Hide full author list

Cancers 2021, 13(18), 4651; https://doi.org/10.3390/cancers13184651 - 16 Sep 2021

Cited by 5 | Viewed by 2740

Abstract

Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small-cell lung cancers (NSCLC) that harbour sensitising mutations within the epidermal growth factor receptor (EGFR). However, resistance remains a key issue, with tumour relapse likely to occur. We have previously identified that cell division [...] Read more.

Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small-cell lung cancers (NSCLC) that harbour sensitising mutations within the epidermal growth factor receptor (EGFR). However, resistance remains a key issue, with tumour relapse likely to occur. We have previously identified that cell division cycle-associated protein 3 (CDCA3) is elevated in adenocarcinoma (LUAD) and correlates with sensitivity to platinum-based chemotherapy. Herein, we explored whether CDCA3 levels were associated with EGFR mutant LUAD and TKI response. We demonstrate that in a small-cohort tissue microarray and in vitro LUAD cell line panel, CDCA3 protein levels are elevated in EGFR mutant NSCLC as a result of increased protein stability downstream of receptor tyrosine kinase signalling. Here, CDCA3 protein levels correlated with TKI potency, whereby CDCA3^high EGFR mutant NSCLC cells were most sensitive. Consistently, ectopic overexpression or inhibition of casein kinase 2 using CX-4945, which pharmacologically prevents CDCA3 degradation, upregulated CDCA3 levels and the response of T790M(+) H1975 cells and two models of acquired resistance to TKIs. Accordingly, it is possible that strategies to upregulate CDCA3 levels, particularly in CDCA3^low tumours or upon the emergence of therapy resistance, might improve the response to EGFR TKIs and benefit patients. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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13 pages, 1123 KiB

Open AccessArticle

A Reversible Shift of Driver Dependence from EGFR to Notch1 in Non-Small Cell Lung Cancer as a Cause of Resistance to Tyrosine Kinase Inhibitors

by Francesca Iommelli, Viviana De Rosa, Cristina Terlizzi, Rosa Fonti, Rosa Camerlingo, Maria Patrizia Stoppelli, C. Allison Stewart, Lauren Averett Byers, David Piwnica-Worms and Silvana Del Vecchio

Cancers 2021, 13(9), 2022; https://doi.org/10.3390/cancers13092022 - 22 Apr 2021

Cited by 5 | Viewed by 1982

Abstract

Notch1 plays a key role in epithelial-mesenchymal transition (EMT) and in the maintenance of cancer stem cells. In the present study we tested whether high levels of activated Notch1 in oncogene-driven NSCLC can induce a reversible shift of driver dependence from EGFR to [...] Read more.

Notch1 plays a key role in epithelial-mesenchymal transition (EMT) and in the maintenance of cancer stem cells. In the present study we tested whether high levels of activated Notch1 in oncogene-driven NSCLC can induce a reversible shift of driver dependence from EGFR to Notch1, and thus causing resistance to EGFR inhibitors. Adherent cells (parental) and tumor spheres (TS) from NSCLC H1975 cells and patient-derived CD133-positive cells were tested for EGFR and Notch1 signaling cascade. The Notch1-dependent modulation of EGFR, NCID, Hes1, p53, and Sp1 were then analyzed in parental cells by binding assays with a Notch1 agonist, DLL4. TS were more resistant than parental cells to EGFR inhibitors. A strong upregulation of Notch1 and a concomitant downregulation of EGFR were observed in TS compared to parental cells. Parental cell exposure to DLL4 showed a dose-dependent decrease of EGFR and a simultaneous increase of NCID, Hes1, p53, and Sp1, along with the dislocation of Sp1 from the EGFR promoter. Furthermore, an enhanced interaction between p53 and Sp1 was observed in TS. In NSCLC cells, high levels of active Notch1 can promote a reversible shift of driver dependence from EGFR to Notch1, leading to resistance to EGFR inhibitors. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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15 pages, 711 KiB

Open AccessArticle

Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy

by Nicole K. Yun, Sherin J. Rouhani, Christine M. Bestvina, Ethan M. Ritz, Brendan A. Gilmore, Imad Tarhoni, Jeffrey A. Borgia, Marta Batus, Philip D. Bonomi and Mary Jo Fidler

Cancers 2021, 13(6), 1426; https://doi.org/10.3390/cancers13061426 - 20 Mar 2021

Cited by 15 | Viewed by 5310

Abstract

Background: First-line treatment for patients with non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor (EGFR) mutation is a tyrosine kinase inhibitor (TKI). Despite higher response rates and prolonged progression free survival (PFS) compared with platinum doublet chemotherapy, [...] Read more.

Background: First-line treatment for patients with non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor (EGFR) mutation is a tyrosine kinase inhibitor (TKI). Despite higher response rates and prolonged progression free survival (PFS) compared with platinum doublet chemotherapy, a subset of these patients do not receive prolonged benefit from these agents. We investigate if the neutrophil-to-lymphocyte ratio (NLR) and other markers of cachexia and chronic inflammation correlate with worse outcomes in these patients. Methods: This study is a retrospective review of 137 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and University of Chicago Medicine from August 2011 to July 2019, with outcomes followed through July 2020. The predictive value of NLR and body mass index (BMI) was assessed at the start of therapy, and after 6 and 12 weeks of treatment by univariable and multivariable analyses. Results: On univariable analysis, NLR ≥ 5 or higher NLR on a continuous scale were both associated with significantly worse PFS and overall survival (OS) at treatment initiation, and after 6 or 12 weeks of treatment. On multivariable analysis, NLR ≥ 5 was associated with increased risk of death at 12 weeks of therapy (HR 3.002, 95% CI 1.282–7.029, p = 0.011), as was higher NLR on a continuous scale (HR 1.231, 95% CI 1.063–1.425, p = 0.0054). There was no difference in PFS and OS and amongst BMI categories though number of disease sites and Eastern Cooperative Oncology Group (ECOG) performance status was associated with worse PFS and OS. Conclusions: Patients with NLR ≥ 5 have a worse median PFS and median OS than patients with NLR < 5. NLR may have value as a predictive biomarker and may be useful for selecting patients for therapy intensification in the front-line setting either at diagnosis or after 12 weeks on therapy. NLR needs to be validated prospectively. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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Review

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12 pages, 278 KiB

Open AccessReview

Ablative Radiotherapy as a Strategy to Overcome TKI Resistance in EGFR-Mutated NSCLC

by Jennifer Novak, Ravi Salgia, Howard West, Miguel A Villalona-Calero, Sagus Sampath, Terence Williams, Victoria Villaflor, Erminia Massarelli, Ranjan Pathak, Marianna Koczywas, Brittney Chau and Arya Amini

Cancers 2022, 14(16), 3983; https://doi.org/10.3390/cancers14163983 - 18 Aug 2022

Cited by 3 | Viewed by 1691

Abstract

Tyrosine kinase inhibitor (TKI) therapy is the recommended first-line treatment for metastatic non-small-cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutation. However, most individuals treated with TKI therapy for EGFR-mutant NSCLC will develop tumor resistance to TKI therapy. Therapeutic [...] Read more.

Tyrosine kinase inhibitor (TKI) therapy is the recommended first-line treatment for metastatic non-small-cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutation. However, most individuals treated with TKI therapy for EGFR-mutant NSCLC will develop tumor resistance to TKI therapy. Therapeutic strategies to overcome TKI resistance are the topic of several ongoing clinical trials. One potential strategy, which has been explored in numerous trials, is the treatment of progressive sites of disease with stereotactic body radiation treatment (SBRT) or stereotactic radiosurgery (SRS). We sought to review the literature pertaining to the use of local ablative radiation therapy in the setting of acquired resistance to TKI therapy and to discuss stereotactic radiation therapy as a strategy to overcome TKI resistance. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

31 pages, 1368 KiB

Open AccessEditor’s ChoiceReview

Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies

by Andreas Koulouris, Christos Tsagkaris, Anna Chiara Corriero, Giulio Metro and Giannis Mountzios

Cancers 2022, 14(14), 3337; https://doi.org/10.3390/cancers14143337 - 08 Jul 2022

Cited by 20 | Viewed by 5153

Abstract

Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context [...] Read more.

Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context of EGFR mutant NSCLC and discuss its clinical and therapeutic implications. EGFR-dependent and independent molecular pathways have the potential to overcome or circumvent the activity of EGFR-targeted agents including the third-generation TKI, osimertinib, negatively impacting clinical outcomes. CNS metastases occur frequently in patients on EGFR-TKIs, due to the inability of first and second-generation agents to overcome both the BBB and the acquired resistance of cancer cells in the CNS. Newer-generation TKIs, TKIs targeting EGFR-independent resistance mechanisms, bispecific antibodies and antibody-drug conjugates or combinations of TKIs with other TKIs or chemotherapy, immunotherapy and Anti-Vascular Endothelial Growth Factors (anti-VEGFs) are currently in use or under investigation in EGFR mutant NSCLC. Liquid biopsies detecting mutant cell-free DNA (cfDNA) provide a window of opportunity to attack mutant clones before they become clinically apparent. Overall, EGFR TKIs-resistant NSCLC constitutes a multifaceted therapeutic challenge. Mapping its underlying mutational landscape, accelerating the detection of resistance mechanisms and diversifying treatment strategies are essential for the management of the disease. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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20 pages, 667 KiB

Open AccessReview

Acquired Mechanisms of Resistance to Osimertinib—The Next Challenge

by Alejandro Ríos-Hoyo, Laura Moliner and Edurne Arriola

Cancers 2022, 14(8), 1931; https://doi.org/10.3390/cancers14081931 - 12 Apr 2022

Cited by 16 | Viewed by 3678

Abstract

EGFR-mutated tumors represent a significant percentage of non-small cell lung cancer. Despite the increasing use of osimertinib, a treatment that has demonstrated an outstanding clinical benefit with a tolerable toxicity profile, EGFR tumors eventually acquire mechanisms of resistance. In the last years, multiple [...] Read more.

EGFR-mutated tumors represent a significant percentage of non-small cell lung cancer. Despite the increasing use of osimertinib, a treatment that has demonstrated an outstanding clinical benefit with a tolerable toxicity profile, EGFR tumors eventually acquire mechanisms of resistance. In the last years, multiple mechanisms of resistance have been identified; however, after progressing on osimertinib, treatment options remain bleak. In this review, we cover the most frequent alterations and potential therapeutic strategies to overcome them. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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21 pages, 803 KiB

Open AccessEditor’s ChoiceReview

The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

by Matteo Canale, Kalliopi Andrikou, Ilaria Priano, Paola Cravero, Luigi Pasini, Milena Urbini, Angelo Delmonte, Lucio Crinò, Giuseppe Bronte and Paola Ulivi

Cancers 2022, 14(5), 1143; https://doi.org/10.3390/cancers14051143 - 23 Feb 2022

Cited by 22 | Viewed by 4412

Abstract

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including [...] Read more.

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including NSCLC. TP53 mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. TP53 mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different TP53 mutations and responses to Epidermal Growth Factor Receptor (EGFR) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of TP53 mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) EGFR-directed, investigating the possible mechanisms of TP53 mutants within the cellular compartments. We also discuss the role of the TP53 mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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43 pages, 3437 KiB

Open AccessReview

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

by Damien Reita, Lucile Pabst, Erwan Pencreach, Eric Guérin, Laurent Dano, Valérie Rimelen, Anne-Claire Voegeli, Laurent Vallat, Céline Mascaux and Michèle Beau-Faller

Cancers 2021, 13(19), 4926; https://doi.org/10.3390/cancers13194926 - 30 Sep 2021

Cited by 50 | Viewed by 8315

Abstract

Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line [...] Read more.

Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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13 pages, 507 KiB

Open AccessReview

Histologic Transformation in EGFR-Mutant Lung Adenocarcinomas: Mechanisms and Therapeutic Implications

by Ranjan Pathak and Victoria M. Villaflor

Cancers 2021, 13(18), 4641; https://doi.org/10.3390/cancers13184641 - 16 Sep 2021

Cited by 10 | Viewed by 2545

Abstract

With the advent of potent EGFR tyrosine kinase inhibitors (TKIs), the treatment landscape of EGFR-mutant lung adenocarcinomas has changed drastically in recent years. However, the development of resistance to EGFR TKIs remains a critical barrier to improving survival in these patients. Histologic transformations [...] Read more.

With the advent of potent EGFR tyrosine kinase inhibitors (TKIs), the treatment landscape of EGFR-mutant lung adenocarcinomas has changed drastically in recent years. However, the development of resistance to EGFR TKIs remains a critical barrier to improving survival in these patients. Histologic transformations to small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and the sarcomatoid phenotype have been increasingly recognized as important mechanisms of resistance. In this article, we summarize the known biological bases for such phenotypic switches in regard to EGFR TKIs and describe novel pathways that might be harnessed to develop effective novel therapies for patients with EGFR-mutant non-small cell lung cancers. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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24 pages, 3895 KiB

Open AccessReview

Targeting the Epidermal Growth Factor Receptor in EGFR-Mutated Lung Cancer: Current and Emerging Therapies

by Karam Khaddour, Sushma Jonna, Alexander Deneka, Jyoti D. Patel, Mohamed E. Abazeed, Erica Golemis, Hossein Borghaei and Yanis Boumber

Cancers 2021, 13(13), 3164; https://doi.org/10.3390/cancers13133164 - 24 Jun 2021

Cited by 32 | Viewed by 11860

Abstract

Epidermal growth factor receptor-targeting tyrosine kinase inhibitors (EGFR TKIs) are the standard of care for patients with EGFR-mutated metastatic lung cancer. While EGFR TKIs have initially high response rates, inherent and acquired resistance constitute a major challenge to the longitudinal treatment. Ongoing work [...] Read more.

Epidermal growth factor receptor-targeting tyrosine kinase inhibitors (EGFR TKIs) are the standard of care for patients with EGFR-mutated metastatic lung cancer. While EGFR TKIs have initially high response rates, inherent and acquired resistance constitute a major challenge to the longitudinal treatment. Ongoing work is aimed at understanding the molecular basis of these resistance mechanisms, with exciting new studies evaluating novel agents and combination therapies to improve control of tumors with all forms of EGFR mutation. In this review, we first provide a discussion of EGFR-mutated lung cancer and the efficacy of available EGFR TKIs in the clinical setting against both common and rare EGFR mutations. Second, we discuss common resistance mechanisms that lead to therapy failure during treatment with EGFR TKIs. Third, we review novel approaches aimed at improving outcomes and overcoming resistance to EGFR TKIs. Finally, we highlight recent breakthroughs in the use of EGFR TKIs in non-metastatic EGFR-mutated lung cancer. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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