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Open AccessEditorial

New Therapeutic Strategies for Lung Cancer

by Philippe Icard, Diane Damotte and Marco Alifano

Cancers 2021, 13(8), 1937; https://doi.org/10.3390/cancers13081937 - 16 Apr 2021

Cited by 5 | Viewed by 1680

Abstract

Non-small cell lung cancer (NSCLC) accounts for approximately 27% of all cancer-related deaths worldwide, thus representing a major health problem [...] Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

Research

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16 pages, 2192 KiB

Open AccessArticle

Integrated Omics Analysis of Non-Small-Cell Lung Cancer Cells Harboring the EGFR C797S Mutation Reveals the Potential of AXL as a Novel Therapeutic Target in TKI-Resistant Lung Cancer

by Tong-Hong Wang, Chih-Ching Wu, Kuo-Yen Huang, Yann-Lii Leu, Shuenn-Chen Yang, Ci-Ling Chen and Chi-Yuan Chen

Cancers 2021, 13(1), 111; https://doi.org/10.3390/cancers13010111 - 31 Dec 2020

Cited by 12 | Viewed by 3509

Abstract

Oncogenic mutations of epidermal growth factor receptor (EGFR) are responsive to targeted tyrosine kinase inhibitor (TKI) treatment in non-small-cell lung cancer (NSCLC). However, NSCLC patients harboring activating EGFR mutations inevitably develop resistance to TKIs. The acquired EGFR C797S mutation is a known mechanism [...] Read more.

Oncogenic mutations of epidermal growth factor receptor (EGFR) are responsive to targeted tyrosine kinase inhibitor (TKI) treatment in non-small-cell lung cancer (NSCLC). However, NSCLC patients harboring activating EGFR mutations inevitably develop resistance to TKIs. The acquired EGFR C797S mutation is a known mechanism that confers resistance to third-generation EGFR TKIs such as AZD9291. In this work, we employed CRISPR/Cas9 genome-editing technology to knock-in the EGFR C797S mutation into an NSCLC cell line harboring EGFR L858R/T790M. The established cell model was used to investigate the biology and treatment strategy of acquired EGFR C797S mutations. Transcriptome and proteome analyses revealed that the differentially expressed genes/proteins in the cells harboring the EGFR C797S mutation are associated with a mesenchymal-like cell state with elevated expression of AXL receptor tyrosine kinase. Furthermore, we presented evidence that inhibition of AXL is effective in slowing the growth of NSCLC cells harboring EGFR C797S. Our findings suggest that AXL inhibition could be a second-line or a potential adjuvant treatment for NSCLC harboring the EGFR C797S mutation. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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17 pages, 1121 KiB

Open AccessArticle

An All-In-One Transcriptome-Based Assay to Identify Therapy-Guiding Genomic Aberrations in Nonsmall Cell Lung Cancer Patients

by Jiacong Wei, Anna A. Rybczynska, Pei Meng, Martijn Terpstra, Ali Saber, Jantine Sietzema, Wim Timens, Ed Schuuring, T. Jeroen N. Hiltermann, Harry. J.M. Groen, Anthonie J. van der Wekken, Anke van den Berg and Klaas Kok

Cancers 2020, 12(10), 2843; https://doi.org/10.3390/cancers12102843 - 1 Oct 2020

Cited by 5 | Viewed by 2715

Abstract

The number of genomic aberrations known to be relevant in making therapeutic decisions for non-small cell lung cancer patients has increased in the past decade. Multiple molecular tests are required to reliably establish the presence of these aberrations, which is challenging because available [...] Read more.

The number of genomic aberrations known to be relevant in making therapeutic decisions for non-small cell lung cancer patients has increased in the past decade. Multiple molecular tests are required to reliably establish the presence of these aberrations, which is challenging because available tissue specimens are generally small. To optimize diagnostic testing, we developed a transcriptome-based next-generation sequencing (NGS) assay based on single primed enrichment technology. We interrogated 11 cell lines, two patient-derived frozen biopsies, nine pleural effusion, and 29 formalin-fixed paraffin-embedded (FFPE) samples. All clinical samples were selected based on previously identified mutations at the DNA level in EGFR, KRAS, ALK, PIK3CA, BRAF, AKT1, MET, NRAS, or ROS1 at the DNA level, or fusion genes at the chromosome level, or by aberrant protein expression of ALK, ROS1, RET, and NTRK1. A successful analysis is dependent on the number of unique reads and the RNA quality, as indicated by the DV200 value. In 27 out of 51 samples with >50 K unique reads and a DV200 >30, all 19 single nucleotide variants (SNVs)/small insertions and deletions (INDELs), three MET exon 14 skipping events, and 13 fusion gene transcripts were detected at the RNA level, giving a test accuracy of 100%. In summary, this lung-cancer-specific all-in-one transcriptome-based assay for the simultaneous detection of mutations and fusion genes is highly sensitive. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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17 pages, 2416 KiB

Open AccessArticle

Positive Effects of Preventive Nutrition Supplement on Anticancer Radiotherapy in Lung Cancer Bearing Mice

by Yu-Ming Liu, Tsung-Han Wu, Yi-Han Chiu, Hang Wang, Tsung-Lin Li, Simon Hsia, Yi-Lin Chan and Chang-Jer Wu

Cancers 2020, 12(9), 2445; https://doi.org/10.3390/cancers12092445 - 28 Aug 2020

Cited by 5 | Viewed by 2990

Abstract

(1) Background: Radiotherapy (RT) is one of the major treatments for non-small cell lung cancer, but RT-associated toxicities usually impede its anticancer effect. Nutrient supplementation has been applied for cancer prevention or a complementary measure to anticancer therapy. Here, we explored the [...] Read more.

(1) Background: Radiotherapy (RT) is one of the major treatments for non-small cell lung cancer, but RT-associated toxicities usually impede its anticancer effect. Nutrient supplementation has been applied for cancer prevention or a complementary measure to anticancer therapy. Here, we explored the influence of total nutrition supplementation before and after cancer occurrence on the anticancer benefit and side effects of RT. (2) Methods: C57BL/6JNarl mice were inoculated with Lewis lung carcinoma cells and then treated with radiotherapy. TNuF, a total nutrition formula, was prescribed by oral gavage. In the preventive groups, TNuF supplementation started from seven days before tumor inoculation. In the complementary groups, TNuF supplementation began after tumor inoculation. (3) Results: TNuF successfully enhanced the anticancer effect of RT against primary tumor and lung metastasis. Additionally, the complementary supplement improved the high serum TNF-α level and the wasting of sartorius muscle in mice receiving RT. In histologic and molecular analysis, TNuF was observed to modulate EGFR, apoptosis, and VEGF and PD-1/PD-L1 pathways. Furthermore, the anticancer benefit of the preventive supplement was comparable to that of the complementary administration. (4) Conclusions: Our results demonstrated that the prescription of the TNuF total nutrition formula before and after cancer diagnosis attains similar benefits in testing subjects with typical anticancer RT. TNuF is also a potential sensitizer to anti-PD-1 immune therapy. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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20 pages, 9324 KiB

Open AccessArticle

Midkine Is a Potential Therapeutic Target of Tumorigenesis, Angiogenesis, and Metastasis in Non-Small Cell Lung Cancer

by Dong Hoon Shin, Jeong Yeon Jo, Sun Ha Kim, Minyoung Choi, Chungyong Han, Beom K. Choi and Sang Soo Kim

Cancers 2020, 12(9), 2402; https://doi.org/10.3390/cancers12092402 - 24 Aug 2020

Cited by 30 | Viewed by 5032

Abstract

Hypoxia-inducible factors (HIFs) induced by reduced O₂ availability activate the transcription of target genes encoding proteins that play important roles in communication between cancer and stromal cells. Cancer cells were incubated under hypoxic conditions: H1299, A549 (NSCLC); Hep3B, HepG2 (HCC); HCT116, CT26 [...] Read more.

Hypoxia-inducible factors (HIFs) induced by reduced O₂ availability activate the transcription of target genes encoding proteins that play important roles in communication between cancer and stromal cells. Cancer cells were incubated under hypoxic conditions: H1299, A549 (NSCLC); Hep3B, HepG2 (HCC); HCT116, CT26 (Colon cancer); MCF-7, MDAMB231 (Breast cancer); MKN1, MKN5 (Gastric cancer); U87MG, SHSY5Y (Brain cancer); and SKOV3, SNU840 (Ovary cancer). All cells expressed HIF-1α and HIF-2α mRNA and proteins. However, cell proliferation of NSCLC, breast, gastric, and brain cancer cells under hypoxia was more dependent on HIF-1α except for HCC cells where it was more dependent on HIF-2α. Among HIF-1α dependent cells H1299 was the most affected in terms of cell proliferation by HIF-1α knockdown. To examine which cytokines are secreted in NSCLC cells by HIF-1α to communicate with stromal cells, we performed a cytokine-profiling array with H1299. We screened the top 14 cytokines which were dependent on the HIF-1α expression pattern. Among them, midkine (MDK) expression was affected the most in response to HIF-1α. MDK is a heparin-binding growth factor that promotes angiogenesis and carcinogenesis. Indeed, MDK significantly increased HUVEV endothelial cell migration and neo- vascularization in chick chorioallantoic membrane assay (CAM) assay via paracrine signaling. In addition, MDK secreted from NSCLC cells interacted with Notch2 which activated the Notch signaling pathway and induced EMT, upregulated NF-κB, and increased cancer promotion. However, in response to MDK knock down, siRNA or the MDK inhibitor, iMDK treatment not only decreased MDK-induced migration and angiogenesis of endothelial cells but also abrogated the progression and metastasis of NSCLC cells in in vitro and in vivo orthotopic and spontaneous lung metastasis models. Consequently, iMDK treatment significantly increased mice survival rates compared with the control or MDK expression group. MDK plays a very important role in the progression and metastasis of NSCLC cells. Moreover, the MDK targeting strategy provides a potential therapeutic target for the treatment of MDK-expressing lung cancers. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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20 pages, 3525 KiB

Open AccessArticle

Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor

by Donatella Romaniello, Ilaria Marrocco, Nishanth Belugali Nataraj, Irene Ferrer, Diana Drago-Garcia, Itay Vaknin, Roni Oren, Moshit Lindzen, Soma Ghosh, Matthew Kreitman, Jeanette Clarissa Kittel, Nadege Gaborit, Gretchen Bergado Baez, Belinda Sanchez, Raya Eilam, Eli Pikarsky, Luis Paz-Ares and Yosef Yarden

Cancers 2020, 12(9), 2394; https://doi.org/10.3390/cancers12092394 - 24 Aug 2020

Cited by 33 | Viewed by 5214

Abstract

Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with [...] Read more.

Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational downregulation of HER3, suppression of MET and AXL upregulation, as well as concomitant inhibition of AKT signaling and upregulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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12 pages, 265 KiB

Open AccessArticle

Normalized Pulmonary Artery Diameter Predicts Occurrence of Postpneumonectomy Respiratory Failure, ARDS, and Mortality

by Elisa Daffrè, Mathilde Prieto, Haihua Huang, Aurélie Janet-Vendroux, Kim Blanc, Yen-Lan N’Guyen, Ludovic Fournel and Marco Alifano

Cancers 2020, 12(6), 1515; https://doi.org/10.3390/cancers12061515 - 10 Jun 2020

Cited by 5 | Viewed by 2101

Abstract

Hypothesizing that pulmonary artery diameter is a marker of subclinical pulmonary hypertension, we assessed its impact on postoperative outcome in patients requiring pneumonectomy. Morphometric, clinical, and laboratory data were retrospectively retrieved from files of 294 consecutive patients treated by pneumonectomy for malignancy (289 [...] Read more.

Hypothesizing that pulmonary artery diameter is a marker of subclinical pulmonary hypertension, we assessed its impact on postoperative outcome in patients requiring pneumonectomy. Morphometric, clinical, and laboratory data were retrospectively retrieved from files of 294 consecutive patients treated by pneumonectomy for malignancy (289 NSCLC). Pulmonary artery was measured at bifurcation level on CT scan and normalized by body surface area. Median normalized pulmonary artery diameter (cut-off for analyses) was 14 mm/m2. Postoperatively, 46 patients required re-do intubation and 30 had acute respiratory distress syndrome (ARDS). Multivariate analysis showed that Charlson Comorbidity Index >5 (p = 0.0009, OR 3.8 [1.76–8.22]), right side of pneumonectomy (p = 0.013, OR 2.37 [1.20–4.71]), and higher normalized pulmonary artery diameter (p = 0.029, OR 2.16 [1.08–4.33]) were independent predictors of re-do intubation, while Charlson Comorbidity Index >5 (p = 0.018, OR 2.55 [1.17–5.59]) and higher normalized pulmonary artery diameter (p = 0.028, OR = 2.52 [1.10–5.77]) were independently associated with occurrence of ARDS. Post-operative mortality was 8.5%. Higher normalized pulmonary artery diameter, (p = 0.026, OR 3.39 [1.15–9.95]), right side of pneumonectomy (p = 0.0074, OR 4.11 [1.46–11.56]), and Charlson Comorbidity Index >5 (p = 0.0011, OR 5.56 [1.99–15.54]) were independent predictors of postoperative death. We conclude that pre-operative normalized pulmonary artery diameter predicts the risk of re-do intubation, ARDS and mortality in patients undergoing pneumonectomy for cancer. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

12 pages, 936 KiB

Open AccessArticle

Stereotactic Radiotherapy for Ultra-Central Lung Oligometastases in Non-Small-Cell Lung Cancer

by Mauro Loi, Davide Franceschini, Luca Dominici, Ciro Franzese, Ilaria Chiola, Tiziana Comito, Marco Marzo, Giacomo Reggiori, Pietro Mancosu, Stefano Tomatis, Joost Nuyttens and Marta Scorsetti

Cancers 2020, 12(4), 885; https://doi.org/10.3390/cancers12040885 - 5 Apr 2020

Cited by 13 | Viewed by 3788

Abstract

Background: Stereotactic body radiotherapy (SBRT) in ultra-central (UC) lung tumors, defined in the presence of planning target volume (PTV) overlap or direct tumor abutment to the central bronchial tree or esophagus, may be correlated to a higher incidence of severe adverse events. Outcome [...] Read more.

Background: Stereotactic body radiotherapy (SBRT) in ultra-central (UC) lung tumors, defined in the presence of planning target volume (PTV) overlap or direct tumor abutment to the central bronchial tree or esophagus, may be correlated to a higher incidence of severe adverse events. Outcome and toxicity in oligometastatic (≤3 metastases) non-small-cell lung cancer (NSCLC) patients receiving SBRT for UC tumors were evaluated. Methods: Oligometastatic NSCLC patients treated with SBRT for UC were retrospectively reviewed. Local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS) were calculated. Incidence and grade of toxicity were evaluated. Statistical analysis was performed to assess the impact of clinical and treatment-related variables on outcome and toxicity occurrence. Results: Seventy-two patients were treated to a median biologically effective dose (BED) of 105 (75–132) Gy¹⁰. Two-year LC, DMFS, PFS, and OS were 83%, 46%, 43%, and 49%. BED>75 Gy¹⁰ was correlated to superior LC (p = 0.02), PFS (p = 0.036), and OS (p < 0.001). Grade ≥3 toxicity rate was 7%, including one fatal esophagitis. No variables were correlated to DMFS or to occurrence of overall and grade ≥3 toxicity. Conclusions: SBRT using dose-intensive schedules improves outcome in NSCLC patients. Overall toxicity is acceptable, although rare but potentially fatal toxicities may occur. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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17 pages, 5773 KiB

Open AccessArticle

The Inhibition of Wnt Restrain KRAS^G12V-Driven Metastasis in Non-Small-Cell Lung Cancer

by Pei-Shan Hung, Ming-Hung Huang, Yuan-Yeh Kuo and James Chih-Hsin Yang

Cancers 2020, 12(4), 837; https://doi.org/10.3390/cancers12040837 - 31 Mar 2020

Cited by 11 | Viewed by 4022

Abstract

The KRAS mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRAS^G12V/KRAS^G12D mutations and inhibited the KRAS^G12V mediated metastasis by [...] Read more.

The KRAS mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRAS^G12V/KRAS^G12D mutations and inhibited the KRAS^G12V mediated metastasis by Wnt inhibitor. First, we found that KRAS^G12V induced more aggressive phenotype in vitro and in vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRAS^G12V cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRAS^G12D induced higher activation of RhoA and suppressed activation of Wnt/β-catenin in H838KRAS^G12D cells. The restored activation of Wnt/β-catenin in H838KRAS^G12D cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRAS^G12V-induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by KRAS mutations. Our data indicate that KRAS^G12V driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRAS^G12V/KRAS^G12D is distinct. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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16 pages, 589 KiB

Open AccessFeature PaperArticle

Pre-Disease and Pre-Surgery BMI, Weight Loss and Sarcopenia Impact Survival of Resected Lung Cancer Independently of Tumor Stage

by Philippe Icard, Olivier Schussler, Mauro Loi, Antonio Bobbio, Audrey Mansuet Lupo, Marie Wislez, Antonio Iannelli, Ludovic Fournel, Diane Damotte and Marco Alifano

Cancers 2020, 12(2), 266; https://doi.org/10.3390/cancers12020266 - 22 Jan 2020

Cited by 39 | Viewed by 3352

Abstract

Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung resection for NSCLC. Methods: A retrospective analysis of a prospectively collected database was made [...] Read more.

Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung resection for NSCLC. Methods: A retrospective analysis of a prospectively collected database was made on 304 consecutive patients. Results: Underweight, normal, overweight and obese patients represented 7.6%, 51.6%, 28.6%, and 12.6% of the pre-disease population. Weight loss and gain were recorded in 44.4% and 5% of patients, respectively. Low muscle mass was more frequently associated with BMI < 25 kg/m² (p < 0.000001). Overall survival was positively affected by pre-disease (p = 0.036) and pre-surgery (p = 0.017) BMI > 25 kg/m², and, even more, in case of BMI > 25 kg/m² and increasing weight (p = 0.012). Long-term outcome was negatively influenced by low muscle mass (p = 0.042) and weight loss (p = 0.0052) as well as age (p = 0.017), ASA categories (p = 0.025), extent of resection (p = 0.0001), pleural invasion (p = 0.0012) and higher pathologic stage (p < 0.0001). Three stepwise multivariable models confirmed the independent favorable prognostic value of higher pre-disease (RR 0.66[0.49–0.89], p = 0.006) and pre-surgery BMI (RR 0.72[0.54–0.98], p = 0.034), and the absence of low muscle mass (RR 0.56[0.37–0.87], p = 0.0091). Conclusions: Body reserves assessed by simple clinical markers impact survival of surgically treated NSCLC. Strategies improving body fat and muscular mass before surgery should be considered. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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Review

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17 pages, 726 KiB

Open AccessReview

Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies

by Alberto D’Angelo, Navid Sobhani, Robert Chapman, Stefan Bagby, Carlotta Bortoletti, Mirko Traversini, Katia Ferrari, Luca Voltolini, Jacob Darlow and Giandomenico Roviello

Cancers 2020, 12(11), 3293; https://doi.org/10.3390/cancers12113293 - 6 Nov 2020

Cited by 55 | Viewed by 11132

Abstract

The treatment of patients affected by non-small cell lung cancer (NSCLC) has been revolutionised by the discovery of druggable mutations. ROS1 (c-ros oncogene) is one gene with druggable mutations in NSCLC. ROS1 is currently targeted by several specific tyrosine kinase inhibitors (TKIs), but [...] Read more.

The treatment of patients affected by non-small cell lung cancer (NSCLC) has been revolutionised by the discovery of druggable mutations. ROS1 (c-ros oncogene) is one gene with druggable mutations in NSCLC. ROS1 is currently targeted by several specific tyrosine kinase inhibitors (TKIs), but only two of these, crizotinib and entrectinib, have received Food and Drug Administration (FDA) approval. Crizotinib is a low molecular weight, orally available TKI that inhibits ROS1, MET and ALK and is considered the gold standard first-line treatment with demonstrated significant activity for lung cancers harbouring ROS1 gene rearrangements. However, crizotinib resistance often occurs, making the treatment of ROS1-positive lung cancers more challenging. A great effort has been undertaken to identify a new generation or ROS1 inhibitors. In this review, we briefly introduce the biology and role of ROS1 in lung cancer and discuss the underlying acquired mechanisms of resistance to crizotinib and the promising new agents able to overcome resistance mechanisms and offer alternative efficient therapies. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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31 pages, 422 KiB

Open AccessReview

Resectable IIIA-N2 Non-Small-Cell Lung Cancer (NSCLC): In Search for the Proper Treatment

by Debora Brascia, Giulia De Iaco, Marcella Schiavone, Teodora Panza, Francesca Signore, Alessandro Geronimo, Doroty Sampietro, Michele Montrone, Domenico Galetta and Giuseppe Marulli

Cancers 2020, 12(8), 2050; https://doi.org/10.3390/cancers12082050 - 25 Jul 2020

Cited by 17 | Viewed by 5067

Abstract

Locally advanced non-small cell lung cancer accounts for one third of non-small cell lung cancer (NSCLC) at the time of initial diagnosis and presents with a wide range of clinical and pathological heterogeneity. To date, the combined multimodality approach involving both local and [...] Read more.

Locally advanced non-small cell lung cancer accounts for one third of non-small cell lung cancer (NSCLC) at the time of initial diagnosis and presents with a wide range of clinical and pathological heterogeneity. To date, the combined multimodality approach involving both local and systemic control is the gold standard for these patients, since occult distant micrometastatic disease should always be suspected. With the rapid increase in treatment options, the need for an interdisciplinary discussion involving oncologists, surgeons, radiation oncologists and radiologists has become essential. Surgery should be recommended to patients with non-bulky, discrete, or single-level N2 involvement and be included in the multimodality treatment. Resectable stage IIIA patients have been the subject of a number of clinical trials and retrospective analysis, discussing the efficiency and survival benefits on patients treated with the available therapeutic approaches. However, most of them have some limitations due to their retrospective nature, lack of exact pretreatment staging, and the involvement of heterogeneous populations leading to the awareness that each patient should undergo a tailored therapy in light of the nature of his tumor, its extension and his performance status. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

24 pages, 1012 KiB

Open AccessReview

Current Strategies for Treating NSCLC: From Biological Mechanisms to Clinical Treatment

by Junnan Li and Hang Fai Kwok

Cancers 2020, 12(6), 1587; https://doi.org/10.3390/cancers12061587 - 15 Jun 2020

Cited by 27 | Viewed by 5350

Abstract

The identification of specific epidermal growth factor receptor (EGFR)-activating mutations heralded a breakthrough in non-small-cell lung cancer (NSCLC) treatments, with the subsequent development of EGFR-tyrosine kinase inhibitor (TKIs) becoming the first-line therapy for patients harboring EGFR mutations. However, acquired resistance to EGFR-TKIs inevitably [...] Read more.

The identification of specific epidermal growth factor receptor (EGFR)-activating mutations heralded a breakthrough in non-small-cell lung cancer (NSCLC) treatments, with the subsequent development of EGFR-tyrosine kinase inhibitor (TKIs) becoming the first-line therapy for patients harboring EGFR mutations. However, acquired resistance to EGFR-TKIs inevitably occurs in patients following initial TKI treatment, leading to disease progression. Various mechanisms are behind the acquired resistance, and mainly include (1) target gene modification, (2) alternative parallel pathway activation, (3) downstream pathway activation, and (4) histological/phenotypic transformation. Approaches to combat the acquired resistance have been investigated according to these mechanisms. Newer generations of TKIs have been developed to target the secondary/tertiary EGFR mutations in patients with acquired resistance. In addition, combination therapies have been developed as another promising strategy to overcome acquired resistance through the activation of other signaling pathways. Thus, in this review, we summarize the mechanisms for acquired resistance and focus on the potential corresponding therapeutic strategies for acquired resistance. Full article

(This article belongs to the Special Issue New Therapeutic Strategies for Lung Cancer)

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