Anaplastic lymphoma kinase (ALK) rearrangement in adult renal cell carcinoma with lung metastasis: a case report and literature review
Anaplastic lymphoma kinase (ALK) rearrangement in adult renal cell carcinoma with lung metastasis: a case report and literature review

Renal cell carcinoma (RCC) with anaplastic lymphoma kinase (ALK) rearrangement is rare, and the genetic profiles of the tumor have not been elucidated. Here, we report a case with recurrent papillary RCC and lung metastasis after nephrectomy for nearly 7 years. The patient first received sunitinib, whereas the drug toxicity was intolerable. Combined Immunohistology (IHC) and fluorescence in situ hybridization (FISH) revealed the patient has an ALK rearrangement, and the patient then was treated with crizotinib. The patient had good tolerance, and a partial response in the target lesions was achieved. In order to further understand the benefit of crizotinib in ALK-rearranged RCC, the patient was detected with whole exome sequencing (WES) to study her genetic profiles. Compared those of RCC cases without ALK rearrangement (nALK-RCC), the patient and nine RCC cases with ALK rearrangement (ALK-RCC) revealed unique genetic characteristics: 1) The common mutations that occurred in RCC were n..... READ ARTICLE

Translational Andrology and Urology DOI: 10.21037/tau-20-1343

Authors: Zhou S, Sun G, Wang J, Zhang H.

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Case StudyKirk SmithALK rearrangement, Renal cell carcinoma, RCC, crizotinib, genomic feature, lung metastasis
Overcoming TKI resistance in fusion-driven NSCLC: new generation inhibitors and rationale for combination strategies
Overcoming TKI resistance in fusion-driven NSCLC: new generation inhibitors and rationale for combination strategies

Targeted therapies lead to acquired resistance through multiple mechanisms. The selective pressure of newer, more potent TKIs results in new resistance mechanisms. Article gives overview of strategies for overcoming resistance to TKIs targeting the common oncogenic gene fusions in NSCLC. READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-2019-cnsclc-06

Authors: Alessandro Russo, Andrés F. Cardona, Christian Caglevic, Paolo Manca, Alejandro Ruiz-Patiño, Oscar Arrieta, Christian Rolfo

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Review PaperKirk SmithALK, RET, acquired resistance, ROS1, NTRK
How to select the best upfront therapy for metastatic disease? Focus on ALK-rearranged non-small cell lung cancer (NSCLC)
How to select the best upfront therapy for metastatic disease? Focus on ALK-rearranged non-small cell lung cancer (NSCLC)

Since then, subsequent generations of ALK inhibitors have demonstrated superior efficacy and better CNS activity compared to crizotinib. Alectinib and brigatinib, both second-generation ALK inhibitors have been compared directly to crizotinib in the first-line setting and has demonstrated improved progression free survival (PFS) and intracranial response. Ceritinib, another second-generation ALK inhibitor has been shown to be superior to chemotherapy in ALK-rearranged disease with good CNS activity. Initial responses to ALK inhibitors are not always durable and resistance can occur as on-target or off-target alterations. Lorlatinib, a third-generation ALK inhibitor, has demonstrated activity in the treatment naïve setting and in resistance to crizotinib and second-generation ALK inhibitors. Lorlatinib has also shown improved PFS in patients harboring EML4-ALK variant 3, which is associated with the development of ALK resistance mutations, specifically G1202R. Another new ALK inhibitor, ensartinib, has demonstrated efficacy in the first-line setting and in alectinib refractory disease. READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-20-331

Authors: Bing Xia, Misako Nagasaka, Viola W. Zhu, Sai-Hong Ignatius Ou, Ross A. Soo

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Real-World OutcomesKirk SmithNSCLC, ALK, TKI, targeted therapy
A case report of exceptional clinical response to chemoradiotherapy and tyrosine kinase inhibitors in a patient with EML4-ALK fusion variant 1 non-small cell lung cancer
A case report of exceptional clinical response to chemoradiotherapy and tyrosine kinase inhibitors in a patient with EML4-ALK fusion variant 1 non-small cell lung cancer

Herein, we report the case of a non-smoking 36-year-old female patient who was diagnosed with right lung adenocarcinoma in 2005 (cT1N3M0, IIIB) and received definitive chemoradiotherapy. The patient achieved a partial response, and her disease remained under control for 8 years. However, in May 2013, the patient was diagnosed with brain metastasis and underwent subsequent surgical resection, followed by postoperative brain radiotherapy and chemotherapy. Postoperative pathology confirmed ALK gene rearrangement, and next-generation sequencing performed in 2020 identified the EML4-ALK variant as variant 1. After progression-free survival lasting 4 years, new metastatic lesions were found in the patient’s right lung, and she was administered crizotinib for 20 months. Due to a suspicious recurrence in the intracranial surgical margin area, as well as an unbearable gastrointestinal reaction to crizotinib, alectinib was later adopted. At the 7-month follow-up, positron emission tomography/com..... READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-20-1212

Authors: Xu X, Liu D, Wen J, Chen J, Fan M.

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Case StudyKirk SmithLung cancer, EML4-ALK, variant 1
Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won
Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won

The bedrock of resistance to TKI is that, after the diagnosis, we face with a different disease that needs to be re-characterized through tissue or/and liquid biopsies. Understanding molecular pathways driving the resistant phenotype will give us the chance to know what we are dealing with and, rather than choose an empirical approach, will help us to properly define the best targeted treatment for these patients. READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-20-372

Authors: Tabbò F, Reale ML, Bironzo P, Scagliotti GV.

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Real-World OutcomesKirk SmithALK, acquired mutations, ALK inhibitor, clonal evolution, resistance
The role of plasma genotyping in ALK- and ROS1-rearranged lung cancer
The role of plasma genotyping in ALK- and ROS1-rearranged lung cancer

Review discusses technical aspects of plasma genotyping strategies and summarize findings from studies exploring plasma genotyping (including ctDNA analysis and profiling of nucleic acids contained in other plasma components) in two rearrangement-driven NSCLC subsets (ALK-rearranged and ROS1-rearranged). READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-2019-cnsclc-09

Authors: Dagogo-Jack I, Ritterhouse LL.

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Review PaperKirk SmithctDNA, next-generation sequencing, NGS, ALK, liquid biopsy
Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression.
Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression.

These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC. READ ARTICLE

Clinical Cancer Research DOI: 10.1158/1078-0432.ccr-20-2853

Authors: Azusa Tanimoto, Shingo Matsumoto, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Akihiro Nishiyama, Kiyotaka Yoh, Takaya Ikeda, Naoki Furuya, Kazumi Nishino, Yuichiro Ohe, Koichi Goto, Seiji Yano

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Pre-ClinicalKirk SmithALK rearrangement, alectinib, p53, Noxa, Mcl-1, apoptosis
Switching to an alternative ALK-inhibitor after alectinib-induced pneumonitis resulted in resolution of this adverse event
Switching to an alternative ALK-inhibitor after alectinib-induced pneumonitis resulted in resolution of this adverse event

This report adds to the available literature and demonstrates that utilizing an alternative ALK-inhibitor may be a potential management strategy for drug-induced ILD/pneumonitis that allows patients to continue to receive these effective therapies. READ ARTICLE

Current Problems in Cancer: Case Reports DOI: 10.1016/j.cpccr.2020.100023

Authors: Evan Bryson, Suresh Ramalingam, Tyler Beardslee

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Case StudyKirk SmithInterstitial lung disease, Pneumonitis, Drug-induced pneumonitis, ALK-inhibitor induced pneumonitis
Longitudinal Health Utilities, Symptoms and Toxicities in Patients with ALK-Rearranged Lung Cancer Treated with Tyrosine Kinase Inhibitors: A Prospective Real-World Assessment
Longitudinal Health Utilities, Symptoms and Toxicities in Patients with ALK-Rearranged Lung Cancer Treated with Tyrosine Kinase Inhibitors: A Prospective Real-World Assessment

There was no significant decrease in HUS when patients with ALK+ disease were treated longitudinally with each TKI, as long as patients were clinically stable. Alectinib, brigatinib, and lorlatinib had the best toxicity profiles and exhibited high mean HUS longitudinally in the real-world setting. READ ARTICLE

Current Oncology DOI: 10.3747/co.27.6563

Authors: Tse BC, Said BI, Fan ZJ, Hueniken K, Patel D, Gill G, Liang M, Razooqi M, Brown MC, Sacher AG, Bradbury PA, Shepherd FA, Leighl NB, Xu W, Howell D, Liu G, O'Kane G.

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Real-World OutcomesKirk Smithhealth utility
Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer
Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, commonly
defined by genetic alterations in oncogenic drivers. Targeted therapies
have transformed the management of oncogene-driven lung cancers, with
targeted agents now approved in the United States for 7 distinct
molecular alterations. Nonetheless, acquired resistance remains an
ongoing challenge, underscoring the need for alternative therapeutic
approaches. Immune checkpoint inhibitors targeting the programmed cell
death 1 (PD-1) axis have emerged as important therapies in the
management of advanced NSCLC, but the role of these agents in patients
with oncogenic driver mutations remains unclear. Here, we focus on
epidermal growth factor receptor-mutant and anaplastic lymphoma
kinase-rearranged NSCLC as paradigms to explore the role of immune
checkpoint inhibitors in oncogene-driven NSCLC. We provide an overview
of the clinical data examining programmed death ligand 1 (PD-L1)
inhibitor monotherapy, PD-(L)1 inhibitors, and tyrosine kinase inhibitor
combinations, as well as combinations of PD-(L)1 inhibitors and
chemotherapy. READ ARTICLE

Cancer Journal DOI:10.1097/PPO.0000000000000491

Authors: Gavralidis A, Gainor JF

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Review PaperKirk SmithALK, EGFR, immunotherapy, oncogenic-driver, PD-1
Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance
Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapymediated activation of NF-kB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy. READ ARTICLE

BioRxIV DOI:10.1101/2020.12.18.423280

Authors: Manasi K. Mayekar, View ORCID ProfileDeborah R. Caswell, Natalie I. Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, D. Lucas Kerr, Julia K. Rotow, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanjo, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nnennaya Kanu, Nicholas McGranahan, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever G. Bivona, Charles Swanton

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Pre-Clinical, Pre-PrintKirk SmithALK, EGFR, NFkB, APOBEC deaminases
Prolonged survival without progression under crizotinib treatment
Prolonged survival without progression under crizotinib treatment

In recent years, serious changes have been observed in the treatment algorithms of especially lung cancer patients. The start-up phase of treatment planning of metastatic lung adenocarcinoma patients is comprised of driver mutation research. Among the pretreatment options of patients diagnosed with EML4-ALK rearrangement, is crizotinib. The group disgnosed with EML4-ALK rearrangement, composes a little part of metastatic non-small cell lung cancer. In this case presented, I will focus on the start of crizotinib treatment and 53-month follow-up in remission in a patient, who has been operated twice and received cisplatin-based adjuvant chemotherapy twice, and relapsed for the second time as Stage-4. READ ARTICLE

Cancer Treatment and Research Communications DOI: 10.1016/j.ctarc.2020.100259

Author: Gulmez A Dr.

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Case StudyKirk SmithCrizotinib, EML4-ALK, Lung cancer
ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients
ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients

It remains unclear how programmed death-ligand 1 (PD-L1) expression interacts with anaplastic lymphoma kinase (ALK) mutation, its variants, and the outcome of treatment. One hundred and twenty four out of 1255 patients (9.9%) were deemed ALK-positive by the Ventana IHC assay. PD-L1 status and ALK variants were available in 100 and 59 patients, respectively. PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rate was 50% and 16%, respectively. A total of 64 variant types were detected in 59 patients. V1 (32.8%) and V3a/b (28.1%) were the most common variants. There was no significant association between ALK variants and the PD-L1 expression. The presence of V3a/b subtype independently predicted a worse overall survival in patients receiving ALK inhibitor(s) (aHR 5.10 [95% CI 1.22–21.25], P = 0.025) and platinum plus pemetrexed (aHR 9.62 [95% CI 1.90–48.80], P = 0.006). While incorporating ALK variants and PD-L1 expression together, patients with non-V3a/b/positive PD-L1 showed a ..... READ ARTICLE

Nature DOI: 10.1038/s41598-020-78152-1

Authors: Manasi K. Mayekar, View ORCID ProfileDeborah R. Caswell, Natalie I. Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, D. Lucas Kerr, Julia K. Rotow, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanjo, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nnennaya Kanu, Nicholas McGranahan, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever G. Bivona, Charles Swanton

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Real-World OutcomesKirk SmithALK variants, PD-L
EML4-ALK-mediated Activation of the JAK2-STAT Pathway is Critical for Non-small Cell Lung Cancer Transformation
EML4-ALK-mediated Activation of the JAK2-STAT Pathway is Critical for Non-small Cell Lung Cancer Transformation

Aberrant expression of EML4-ALK leads to JAK2-STAT signaling pathway activation, an essential part of the development of non-small cell lung cancer. READ ARTICLE

BMC Pulmonary Medicine DOI: https://doi.org/10.1186/s12890-021-01553-z

Authors: Ying Li, Yongwen Li, Hongbing Zhang, Ruifeng Shi, Zihe Zhang, Hongyu Liu, Jun Chen

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Pre-ClinicalKirk SmithEML4-ALK, JAK2-STAT pathway, transformation, NSCLC
What Is the Standard First-Line Treatment for Advanced Non-Small Cell Lung Cancer?
What Is the Standard First-Line Treatment for Advanced Non-Small Cell Lung Cancer?

The initial treatment regimens for advanced non-small cell lung cancer (NSCLC) have drastically evolved over the last 15 years with the rapid development of improved genomic sequencing technologies and the emergence of immune checkpoint inhibitors. Highly active oral kinase inhibitors are now approved for several molecularly defined subsets of NSCLC, including those harboring alterations in the EGFR, ALK, ROS1, BRAF, MET, RET, and NTRK genes, although acquired resistance to these targeted therapies remains a significant clinical challenge. In lung cancers lacking targetable mutations, programmed death 1/programmed death ligand 1 immune checkpoint inhibitors, used alone or in combination with cytotoxic T-lymphocyte-associated protein 4 inhibitors and/or cytotoxic chemotherapy, have led to meaningful improvements in overall survival. With many therapeutic options available to patients, here we review the recommended frontline treatment regimens for advanced NSCLC with and without targetable genomic drivers. READ ARTICLE

Cancer (Journal) DOI: 10.1097/PPO.0000000000000489

Authors: Ricciuti B, Awad MM.

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Review PaperKirk SmithALK, therapeutic options
PROTACs: A novel strategy for cancer therapy
PROTACs: A novel strategy for cancer therapy

Chemotherapeutic strategy has been widely used for treating malignance by targeting irregular expressed or mutant proteins with small molecular inhibitors (SMIs) or monoclonal antibodies (mAbs). However, most intracellular proteins lack of active sites or antigens where SMIs or mAbs bind with, and are called as non-druggable targets for a long time. From the first year of this century, PROteolysis-TArgeting Chimeras (PROTACs) has emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. The first generation of peptide-based PROTACs adopts β-TrCP and VHL as E3 ligases, but the cellular permeability and chemical stability issues restrict their clinical application. The second generation of small molecule-based PROTACs adopts MDM2, VHL, IAPs and Cereblon as E3 ligases have been tensely studied. To date, the targets of PROTACs including those overexpressed oncogenic proteins such as ER, AR and BRDs, disease-r..... READ ARTICLE

Seminars in Cancer Biology DOI:10.1016/j.semcancer.2020.02.006

Authors: Jing Liu, Jia Ma, Yi Liua, Jun Xia, Yuyun Li, Z. Peter Wang, Wenyi Wei

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Conference PaperKirk SmithPROTACs, Cancer, Therapyopto-PROTAC, pcPROTAC, PHOTAC, Photo-PROTAC
Functional coding/non-coding variants in EGFR, ROS1 and ALK genes and their role in liquid biopsy as a personalized therapy
Functional coding/non-coding variants in EGFR, ROS1 and ALK genes and their role in liquid biopsy as a personalized therapy

Personalized medicine holds promise to tailor the treatment options for patients’ unique genetic make-up, behavioral and environmental background. Liquid biopsy is non-invasive technique and precise diagnosis and treatment approach. Significantly, NGS technologies have revolutionized the genomic medicine by novel identifying SNPs, indel mutations in both coding and non-coding regions and also a promising technology to accelerate the early detection and finding new biomarkers for diagnosis and treatment. The number of the bioinformatics tools have been rapidly increasing with the aim of learning more about the detected mutations either they have a pathogenic role or not. EGFR, ROS1 and ALK genes are members of the RTK family. Until now, mutations within these genes have been associated with many cancers and involved in resistance formation to TKIs. This review article summarized the findings about the mostly investigated variations in EGFR, ROS1 and ALK genes and their potential role in..... READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.103113

Authors: Mahmut Cerkez Ergoren, Havva Cobanogulları, Sehime Gulsun Temel, Gamze Mocan

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Review PaperKirk SmithEGFR, ROS1, ALK, Tyrosine kinase inhibitors, Liquid biopsy, Personalized therapy
Clinicopathological features and immunohistochemical utility of NTRK-, ALK-, and ROS1-rearranged papillary thyroid carcinomas and anaplastic thyroid carcinomas
Clinicopathological features and immunohistochemical utility of NTRK-, ALK-, and ROS1-rearranged papillary thyroid carcinomas and anaplastic thyroid carcinomas

NTRK1/3, ALK, and ROS1 translocations have been reported in a minor subset of papillary thyroid carcinomas (PTCs). We aimed to elucidate the prevalence and clinicopathological characteristics of these gene rearrangements and the utility of immunohistochemistry (IHC) in PTC and anaplastic thyroid carcinoma (ATC). We screened nonradiation-exposed cases of 307 PTCs and 16 ATCs by IHC for pan-Trk, ALK, and ROS1, followed by fluorescence in situ hybridization (FISH). In the PTC group, IHC for pan-Trk, ALK, and ROS1 was positive in 18 cases (5.9%), 1 case (0.3%), and 12 cases (3.9%), respectively. Among the pan-Trk IHC–positive cases (n = 18), 2 cases (11.1%; 0.7% of all PTCs) had NTRK1 or NTRK3 gene rearrangement with conventional PTC histology. The ALK IHC–positive case (n = 1) was the follicular variant of PTC with consistent ALK gene rearrangement. ROS1 gene rearrangement was not detectable in the ROS1 IHC–positive PTCs (0/12) by FISH. Most (approximately 70%) of the pan-Trk or ROS1 IHC–..... READ ARTICLE

Human Pathology DOI:10.1016/j.humpath.2020.09.004

Authors: Yui Nozaki, Hidetaka Yamamoto, Takeshi Iwasaki, Masanobu Sato, Rina Jiromaru, Takahiro Hongo, Ryuji Yasumatsu, Yoshinao Oda

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Case StudyKirk SmithPapillary thyroid carcinoma, Anaplastic thyroid carcinoma, pan-Trk, NTRK, ALK, ROS1
Identification of novel bioactive molecules from garlic bulbs: A special effort to determine the anticancer potential against lung cancer with targeted drugs
Identification of novel bioactive molecules from garlic bulbs: A special effort to determine the anticancer potential against lung cancer with targeted drugs

... Garlic is used in the treatment of various ailments such as cancer, diabetes and cardiovascular diseases. The present study aims to explore the plausible mechanisms of the selected phytocompounds as potential inhibitors against the known drug targets of non-small-cell lung cancer (NSCLC)... The result of this study suggest that these identified phytocompounds from garlic would serve as promising leads for the development of lead molecules to design new multi-targeting drugs to address the different clinical forms of NSCLC. READ ARTICLE

Saudi Journal of Biological Sciences DOI:10.1016/j.sjbs.2020.09.041

Authors: R. Padmini, V. Uma Maheshwari, P.Saravanan, Keun Woo Lee, M. Razia, Mona S. Alwahibi, B. Ravindran, Mohamed Soliman Elshikh, Young Ock Kim, Hyungsuk Kim, Hak-Jae Kim

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Case StudyKirk SmithDocking, Garlic, Inhibitors, Lung cancer, Molecular dynamics simulations