• echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)
• ephrin type-A receptor 2 (EphA2)
• mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2)
• p90 ribosomal S6 kinase (RSK)

• Humans
• Lung Neoplasms/metabolism
• Receptor, EphA2/metabolism
• Protein Serine-Threonine Kinases/metabolism
• Protein Serine-Threonine Kinases/antagonists & inhibitors
• Cell Line, Tumor
• Cell Movement/drug effects
• Intracellular Signaling Peptides and Proteins/metabolism
• Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
• Oncogene Proteins, Fusion/metabolism
• Oncogene Proteins, Fusion/genetics
• Phosphorylation
• Ribosomal Protein S6 Kinases, 90-kDa/metabolism
• Extracellular Signal-Regulated MAP Kinases/metabolism

• cancer therapeutic resistance
• growth factor signalling

• Animals
• Humans
• Mice
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• GRB2 Adaptor Protein/metabolism
• GRB2 Adaptor Protein/genetics
• Intercellular Signaling Peptides and Proteins/metabolism
• Intercellular Signaling Peptides and Proteins/genetics
• Oncogene Proteins, Fusion/metabolism
• Oncogene Proteins, Fusion/genetics
• Optogenetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Receptor Protein-Tyrosine Kinases/genetics
• Signal Transduction/drug effects

• P30 CA008748 NCI NIH HHS
• R01 CA279180 NCI NIH HHS
• RSG-22-176-01-TBE American Cancer Society (American Cancer Society, Inc.)

• anticancer compounds
• drug delivery
• indole
• nanoparticles

• AICAR
• ER stress
• HGF
• NAFLD
• NF-κB
• SIRT2
• SNARK
• mitochondria

• non-small-cell lung cancer
• cancer therapeutic resistance
• targeted therapies

• MET amplification
• NSCLC
• TKIs
• combined-therapy
• detection
• diagnosis
• resistance mechanism

The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%‐5% of patients with non–small cell lung cancer (NSCLC) and confers sensitivity to ALK–tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK‐rearranged NSCLC, various additional ALK‐TKIs have been developed. Ceritinib is a second‐generation ALK‐TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first‐generation ALK‐TKI)‐refractory ALK‐rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib‐resistant, echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK–positive H3122 cells and ceritinib‐resistant patient‐derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib‐resistant patient‐derived specimens confirmed that tyrosine‐protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms.

• ALK Kinase
• Drug Resistance
• ceritinib, FGFR3, lung cancer

In general, the non-Hodgkin lymphoma (NHL), anaplastic large cell lymphoma (ALCL) diagnosed in childhood has a good survival outcome when treated with multi-agent chemotherapy. However, side effects of treatment are common, and outcomes are poorer after relapse, which occurs in up to 30% of cases. New drugs are required that are more effective and have fewer side effects. Targeted therapies are potential solutions to these problems, however, the development of resistance may limit their impact. This review summarises the potential resistance mechanisms to these targeted therapies.

Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.

• anaplastic large cell lymphoma
• chemotherapy
• nucleophosmin1-anaplastic lymphoma kinase
• paediatric cancer
• resistance

• ALK
• ALK-TKI
• NSCLC
• alectinib
• brigatinib
• ceritinib
• lorlatinib
• resistance

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in regulating cell growth, survival, and metastasis. STAT3 signaling is constitutively activated in various types of hematologic or solid malignancies. YHO-1701 has been developed as an orally available STAT3 inhibitor. Herein, YHO-1701 in combination with molecular-targeted agents was evaluated. Additive or synergistic effects were observed in a broad spectrum of “combination treatment + cell line” pairs. Of particular interest was the synergistic effect observed when YHO-1701 was combined with imatinib or dasatinib [breakpoint cluster region-abelson (BCR-ABL) inhibitors], osimertinib [epidermal growth factor receptor (EGFR) inhibitor], crizotinib, alectinib, or ceritinib [anaplastic lymphoma kinase (ALK) inhibitors]. The results further showed a close relationship between these synergistic effects and the cellular levels of the key molecules involved in the target pathways for YHO-1701 and each combination drug. The combination of YHO-1701 with alectinib resulted in significantly greater antitumor activity without exhibiting body weight loss in an NCI-H2228 [echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion] xenograft mouse model. Our results strongly suggest that the logical strategy in combination with the novel STAT3 inhibitor YHO-1701 and other mechanistically different targeted agents, could be a promising approach in future clinical settings.

Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an important cause of alectinib resistance. Furthermore, Gab1 was a key effector in the HGF/MET signal transduction pathway that mediated alectinib resistance. The antidiabetic drug metformin combined with alectinib overcame alectinib resistance triggered by HGF/MET through disrupting the complex between MET and Gab1, thereby inhibiting Gab1 phosphorylation and the activation of downstream signal transduction pathways. These results suggest that metformin combined with alectinib may be useful for overcoming alectinib resistance induced by the activation of the HGF/MET signalling pathway and improving the efficacy of alectinib.

• Non-small-cell lung cancer (NSCLC)
• circulating tumor DNA (ctDNA)
• drug resistance
• epidermal growth factor receptor (EGFR)
• immunotherapy

• ALK-TKI
• MET
• Mutation
• NGS
• Sequential treatment

• Dihydrofolate Reductase (DHFR)
• Heat Shock Protein 90 (HSP90) Inhibitor
• Luminespib (AUY922)
• Non-small cell lung cancer (NSCLC)
• Pemetrexed
• Targeted therapy

Determination of therapeutic efficacy is a major challenge in developing treatment options for cancer. Prior to in vivo studies, candidate therapeutics are evaluated using cell-based in vitro methods to assess their anti-cancer potential. This review describes the utility and limitations of evaluating therapeutic efficacy using human tumor-derived cell lines. Indicators for therapeutic efficacy using tumor-derived cell lines include cell viability, cell proliferation, colony formation, cytotoxicity, cytostasis, induction of apoptosis, and cell cycle arrest. Cell panel screens, 3D tumor spheroid models, drug-drug/drug-radiation combinatorial analysis, and invasion/migration assays reveal analogous in vitro information. In animal models, cellular assays can assess tumor micro-environment and therapeutic delivery. The utility of tumor-derived cell lines for efficacy determination is manifest in numerous commercially approved drugs that have been applied in clinical management of cancer. Studies reveal most tumor-derived cell lines preserve the genomic signature of the primary tumor source and cell line-based data is highly predictive of subsequent clinical studies. However, cell-based data often disregards natural system components, resulting in cell autonomous outcomes. While 3D cell culture platforms can counter such limitations, they require additional time and cost. Despite the limitations, cell-based methods remain essential in early stages of anti-cancer drug development.

• bioassay approaches
• in vivo/in vitro correlation
• pharmaceutical analysis

• ALCL, anaplastic extensive cell lymphoma
• ALK inhibitors
• ALK, anaplastic lymphoma kinase
• ALTA-1L, ALK in lung cancer trial of Brigatinib in1st Line
• BCRP, breast cancer resistance protein
• Brigatinib
• DMPO, dimethyl phosphine oxide
• EGFR, epidermal growth factor receptor
• EML4, echinoderm microtubule associated protein
• FDA, Food and Drug Administration
• FLT3, fem like tyrosine kinase-3
• Kinase
• LCC, Large Cell Carcinoma
• Lung cancer
• Lymphoma
• MIC, minimum inhibitory concentration
• NPM, nucleophosmin
• NSCLC, non-small cell lung cancer
• ORR, objective response rate
• P-gp, P-glycoprotein
• SAR, structure activity relationship
• TKI’s, tyrosine kinase inhibitors

• TKI
• inhibitor
• lung cancer
• molecularly-targeted therapies
• resistance

• alectinib
• antineoplastic agents
• carcinoma, non-small-cell lung

The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and many kinds of ALK fusion genes have been found in a variety of carcinomas. There is almost no detectable expression of ALK in adults. However, through ALK gene rearrangement, the resultant ALK fusion protein is aberrantly overexpressed and dimerized through the oligomerization domains, such as the coiled‐coil domain, in the fusion partner that induces abnormal constitutive activation of ALK tyrosine kinase. This results in dysregulated cell proliferation. ALK gene rearrangement has been observed in 3%‐5% of non‐small‐cell lung cancers, and multiple ALK inhibitors have been developed for the treatment of ALK‐positive lung cancer. Among those inhibitors, in Japan, 3 (4 in the USA) ALK tyrosine kinase inhibitors (TKIs) have been approved and are currently used in clinics. All of the currently approved ALK‐TKIs have been shown to induce marked tumor regression in ALK‐rearranged non‐small‐cell lung cancer; however, tumors inevitably relapse because of acquired resistance within a few years. This review focuses on ALK‐TKIs, their resistance mechanisms, and the potential therapeutic strategies to overcome resistance.

• ALK
• fusion gene
• mutation
• resistance
• tyrosine kinase inhibitor

• cathepsin B
• degradable polymer
• geldanamycin
• polymer-drug conjugates
• prostate cancer

Small‐cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Hence, novel therapeutic strategies for the treatment of SCLC are urgently required. Accordingly, several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion. Here, we found that the HGF/MET signaling was aberrantly activated in chemoresistant or chemorelapsed SCLC cell lines (SBC‐5, DMS273, and DMS273‐G3H) by the secretion of HGF and/or MET copy number gain. A cell‐based in vitro assay revealed that HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA‐mediated knockdown of HGF or MET, constrained growth of chemoresistant SCLC cells through the inhibition of ERK and AKT signals. Furthermore, treatment with either crizotinib or golvatinib suppressed the systemic metastasis of SBC‐5 cell tumors in natural killer cell‐depleted SCID mice, predominantly through cell cycle arrest. These findings reveal the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells showing aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET‐mediated signaling in SCLC cells.

• Animal model
• HGF
• MET
• small-cell lung cancer
• targeted therapy

• Biomarkers
• Federal drug agency
• Lung cancer treatment
• Non-small cell lung cancer

• Early clinical trials
• Hsp27 inhibitors
• Hsp70 inhibitors
• Hsp90 inhibitors
• non-small cell lung cancer

• ALK
• Fusion gene
• Mutation
• Resistance
• Tyrosine kinase inhibitor

• Amphiregulin
• EML4-ALK
• crizotinib-resistance
• epidermal growth factor receptor
• lung cancer

• Amphiregulin/deficiency
• Amphiregulin/genetics
• Amphiregulin/metabolism
• Anaplastic Lymphoma Kinase
• Animals
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Cell Cycle Proteins/metabolism
• Cell Line, Tumor
• Crizotinib
• Disease Models, Animal
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Erlotinib Hydrochloride
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Male
• Mice
• Microtubule-Associated Proteins/metabolism
• Mutation
• Pleural Effusion
• Pleural Neoplasms
• Protein Kinase Inhibitors/pharmacology
• Pyrazoles/pharmacology
• Pyridines/pharmacology
• RNA, Small Interfering/genetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Serine Endopeptidases/metabolism
• Xenograft Model Antitumor Assays

Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms were explored such as genetic alterations, activation of bypass signaling, and phenotypic transition. These intrinsic and/or extrinsic dynamic regulations facilitate tumor cell survival in meeting the demands of signaling under different stimulus. This review introduces lung cancer plasticity and heterogeneity and their correlation with drug resistance. While cancer plasticity and heterogeneity play an essential role in the development of drug resistance, the manipulation of them may bring some inspirations to cancer prognosis and treatment. That is to say, lung cancer plasticity and heterogeneity present us with not only challenges but also opportunities.

• drug resistance
• heterogeneity
• lung cancer
• phenotypic transition
• plasticity

Surgery combined with chemotherapy is an important therapy for non-small cell lung cancer (NSCLC). However, chemotherapy drug resistance seriously hinders the curative effect. Studies show that DNA repair genes ERCC1 and BRCA1 are associated with NSCLC chemotherapy, but their expression and mechanism in NSCLC chemotherapy drug-resistant cells has not been elucidated.

NSCLC cell line A549 and drug resistance cell line A549/DDP were cultured. Real-time PCR and Western blot analyses were used to detect ERCC1 and BRCA1 mRNA expression. A549/DDP cells were randomly divided into 3 groups: the control group; the siRNA-negative control group (scramble group); and the siRNA ERCC1 and BRCA1siRNA transfection group. Real-time PCR and Western blot analyses were used to determine ERCC1 and BRCA1 mRNA and protein expression. MTT was used to detect cell proliferation activity. Caspase 3 activity was tested by use of a kit. Western blot analysis was performed to detect PI3K, AKT, phosphorylated PI3K, and phosphorylated AKT protein expression.

ERCC1 and BRCA1 were overexpressed in A549/DDP compared with A549 (P<0.05). ERCC1 and BRCA1siRNA transfection can significantly reduce ERCC1 and BRCA1 mRNA and protein expression (P<0.05). Downregulating ERCC1 and BRCA1 expression obviously inhibited cell proliferation and increased caspase 3 activity (P<0.05). Downregulating ERCC1 and BRCA1 significantly decreased PI3K and AKT phosphorylation levels (P<0.05).

ERCC1 and BRCA1 were overexpressed in NSCLC drug-resistant cells, and they regulated lung cancer occurrence and development through the phosphorylating PI3K/AKT signaling pathway.

A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

• EGFR
• MLH1
• lung adenocarcinoma
• resistance
• tyrosine kinase inhibitor

• Fusion
• Kinase
• Lung cancer
• Oncogene
• Structural biology

• Anaplastic Lymphoma Kinase
• Animals
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Cell Cycle Proteins/analysis
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• HSP90 Heat-Shock Proteins/antagonists & inhibitors
• Humans
• Lung/metabolism
• Lung/pathology
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Microtubule-Associated Proteins/analysis
• Microtubule-Associated Proteins/genetics
• Microtubule-Associated Proteins/metabolism
• Models, Molecular
• Molecular Targeted Therapy
• Oncogene Proteins, Fusion/analysis
• Oncogene Proteins, Fusion/genetics
• Oncogene Proteins, Fusion/metabolism
• Protein Conformation
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Receptor Protein-Tyrosine Kinases/analysis
• Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
• Receptor Protein-Tyrosine Kinases/genetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Serine Endopeptidases/analysis
• Serine Endopeptidases/genetics
• Serine Endopeptidases/metabolism

• 12772 Cancer Research UK
• 13-0042 Worldwide Cancer Research
• 16-0119 Worldwide Cancer Research
• C24461/A12772 Cancer Research UK

The hepatocyte growth factor receptor (HGFR or c-Met) is a driver of multiple cancer subtypes. While there are several c-Met inhibitors in development, few have been approved for clinical use, warranting the need for continued research and development of c-Met targeting therapeutic modalities. The research presented here demonstrates a particular class of compounds known as isothiocyanatostilbenes can act as c-Met inhibitors in multiple cancer cell lines. Specifically, we found that 4,4′-Diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) and 4,4′-Diisothiocyanatodihydrostilbene-2,2′-disulfonic acid (H2DIDS) had c-Met inhibitory effective doses in the low micromolar range while 4-acetamido-4′-isothiocyanatostilbene-2,2′-disulfonic acid (SITS) and 4,4′-dinitrostilbene-2, 2′-disulfonic acid (DNDS) exhibited IC₅₀s 100 to 1000 fold higher. These compounds displayed much greater selectivity for inhibiting c-Met activation compared to similar receptor tyrosine kinases. In addition, DIDS and H2DIDS reduced hepatocyte growth factor (HGF)-induced, but not epidermal growth factor (EGF)-induced, cell scattering, wound healing, and 3-dimensional (3D) proliferation of tumor cell spheroids. In-cell and cell-free assays suggested that DIDS and H2DIDS can inhibit and reverse c-Met phosphorylation, similar to SU11274. Additional data demonstrated that DIDS is tolerable in vivo. These data provide preliminary support for future studies examining DIDS, H2DIDS, and derivatives as potential c-Met therapeutics.

• DIDS
• H2DIDS
• c-Met
• isothiocyanatostilbenes

• anaplastic lymphoma kinase
• alk
• non-small cell lung cancer
• lung adenocarcinoma
• tyrosine kinase inhibitor
• tki
• clinical trials
• acquired resistance

• Anaplastic Lymphoma Kinase
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/enzymology
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/mortality
• Carcinoma, Non-Small-Cell Lung/pathology
• Clinical Trials as Topic
• Drug Resistance, Neoplasm/genetics
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/enzymology
• Lung Neoplasms/genetics
• Lung Neoplasms/mortality
• Lung Neoplasms/pathology
• Molecular Targeted Therapy
• Mutation
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
• Receptor Protein-Tyrosine Kinases/genetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Recombination, Genetic
• Translocation, Genetic
• Treatment Outcome

• P01 CA129243 NCI NIH HHS
• R01 CA121210 NCI NIH HHS
• P01CA129243 NCI NIH HHS
• R01CA121210 NCI NIH HHS

• Anaplastic Lymphoma Kinase
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Cell Line, Tumor
• Crizotinib
• Drug Resistance, Neoplasm/genetics
• ErbB Receptors/genetics
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Pyrazoles/pharmacology
• Pyrazoles/therapeutic use
• Pyridines/pharmacology
• Pyridines/therapeutic use
• Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
• Receptor Protein-Tyrosine Kinases/genetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Receptor, ErbB-2/genetics
• Receptors, Purinergic P2Y/genetics
• Signal Transduction/drug effects
• Signal Transduction/genetics

• NIH R01 CA154480 NCI NIH HHS
• R01 GM074024 NIGMS NIH HHS
• U54 HG003067 NHGRI NIH HHS
• #5U54HG003067-11 NHGRI NIH HHS
• GM074024 NIGMS NIH HHS
• U54 HG006093 NHGRI NIH HHS
• NIH R01 CA136851 NCI NIH HHS
• T32 CA009172 NCI NIH HHS
• P01 CA154303 NCI NIH HHS
• U01 CA176058 NCI NIH HHS
• DP2 0D002750 NCCDPHP CDC HHS
• R33 CA155554 NCI NIH HHS
• R01 CA154480 NCI NIH HHS
• U54 CA112962 NCI NIH HHS
• NIH 5R33CA155554-03 NCI NIH HHS
• R01 CA121941 NCI NIH HHS
• R01 CA136851 NCI NIH HHS