Five‐year lung cancer survival

Wang, Tina; Nelson, Rebecca A.; Bogardus, Alicia; Grannis, Frederic W.

doi:10.1002/cncr.24871

Cited by 138 publications

(55 citation statements)

References 50 publications

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“…Patients diagnosed with advanced stage non-small cell lung cancer (NSCLC)—which accounts for over 85% of lung cancer diagnoses—have only a 6% chance of survival at 5 years (2). Over the last decade many new oncogenes, primarily activated receptor tyrosine kinases (RTKs), capable of driving NSCLC have been identified leading to the development and successful clinical use of a number of small-molecule therapies (3).…”

Section: Introductionmentioning

confidence: 99%

Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling

Nelson-Taylor¹,

Le²,

Yoo³

et al. 2017

Molecular Cancer Therapeutics

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Oncogenic rearrangements in RET are present in 1-2% of lung adenocarcinoma (LAD) patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent anti-proliferative activity in RET fusion positive LC-2/ad LAD cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose-escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived. PR1 and PR2 cell lines retained expression, but not phosphorylation of the RET fusion and lacked evidence of a resistance mutation in the RET kinase domain. Both resistant lines retained activation of the MAPK pathway. Next-generation RNA sequencing revealed an oncogenic NRAS p.Q61K mutation in the PR1 cell. PR1 cell proliferation was preferentially sensitive to siRNA knockdown of NRAS compared to knockdown of RET, more sensitive to MEK inhibition than the parental line, and NRAS-dependence was maintained in the absence of chronic RET inhibition. Expression of NRAS p.Q61K in RET fusion expressing TPC1 cells conferred resistance to ponatinib. PR2 cells exhibited increased expression of EGFR and AXL. EGFR inhibition decreased cell proliferation and phosphorylation of ERK1/2 and AKT in PR2 cells but not LC-2/ad cells. Although AXL inhibition enhanced PR2 sensitivity to afatinib, it was unable to decrease cell proliferation by itself. Thus, EGFR and AXL cooperatively rescued signaling from RET inhibition in the PR2 cells. Collectively, these findings demonstrate that resistance to ponatinib in RET-rearranged LAD is mediated by bypass signaling mechanisms that result in restored RAS/MAPK activation.

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Section: Introductionmentioning

confidence: 99%

Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling

Nelson-Taylor¹,

Le²,

Yoo³

et al. 2017

Molecular Cancer Therapeutics

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“…Currently, the majority of patients with non–small-cell lung cancer (NSCLC) present with inoperable, locally advanced (stage IIIB) or metastatic (stage IV) disease for which no curative therapy is available, and the 5-year survival rate has remained ≤5% for the last few decades [1,2]. In patients with advanced or metastatic NSCLC without certain cytogenetic abnormalities (e.g.…”

Section: Introductionmentioning

confidence: 99%

Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer

et al. 2014

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BackgroundThe efficacy and safety of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non–small-cell lung cancer (NSCLC).MethodsOverall, 170 patients were randomly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 of up to six 21-day cycles (arm I); axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin (arm II); or pemetrexed/cisplatin alone (arm III). The primary endpoint was progression-free survival (PFS).ResultsMedian PFS was 8.0, 7.9, and 7.1 months in arms I, II, and III, respectively (hazard ratio: arms I vs. III, 0.89 [P = 0.36] and arms II vs. III, 1.02 [P = 0.54]). Median overall survival was 17.0 months (arm I), 14.7 months (arm II), and 15.9 months (arm III). Objective response rates (ORRs) for axitinib-containing arms were 45.5% (arm I) and 39.7% (arm II) compared with 26.3% for pemetrexed/cisplatin alone (arm III). Gastrointestinal disorders and fatigue were frequently reported across all treatment arms. The most common all-causality grade ≥3 adverse events were hypertension in axitinib-containing arms (20% and 17%, arms I and II, respectively) and fatigue with pemetrexed/cisplatin alone (16%).ConclusionAxitinib in combination with pemetrexed/cisplatin was generally well tolerated. Axitinib combinations resulted in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC.Trial registrationClinicalTrials.gov: NCT00768755 (October 7, 2008).

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“…The latter group is further histologically subdivided into four categories; adenocarcinoma, squamous cell carcinoma, large cell carcinoma and 'others', for example cancers of neuroendocrine origin [2]. The overall 5-year survival rate for NSCLC ranges from 9% to 15% [3]. The high mortality from lung cancer is due a combination of lack of reliable early diagnostic tools [3,4] along with a poor arsenal of lung cancer regimens for stage I lung cancer, whose survival rate is also surprisingly low [5].…”

Section: Introductionmentioning

confidence: 99%

A novel in silico reverse-transcriptomics-based identification and blood-based validation of a panel of sub-type specific biomarkers in lung cancer

et al. 2013

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Lung cancer accounts for the highest number of cancer-related deaths worldwide. Early diagnosis significantly increases the disease-free survival rate and a large amount of effort has been expended in screening trials and the development of early molecular diagnostics. However, a gold standard diagnostic strategy is not yet available. Here, based on miRNA expression profile in lung cancer and using a novel in silico reverse-transcriptomics approach, followed by analysis of the interactome; we have identified potential transcription factor (TF) markers that would facilitate diagnosis of subtype specific lung cancer. A subset of seven TF markers has been used in a microarray screen and was then validated by blood-based qPCR using stage-II and IV non-small cell lung carcinomas (NSCLC). Our results suggest that overexpression of HMGA1, E2F6, IRF1, and TFDP1 and downregulation or no expression of SUV39H1, RBL1, and HNRPD in blood is suitable for diagnosis of lung adenocarcinoma and squamous cell carcinoma sub-types of NSCLC. Here, E2F6 was, for the first time, found to be upregulated in NSCLC blood samples. The miRNA-TF-miRNA interaction based molecular mechanisms of these seven markers in NSCLC revealed that HMGA1 and TFDP1 play vital roles in lung cancer tumorigenesis. The strategy developed in this work is applicable to any other cancer or disease and can assist in the identification of potential biomarkers.

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Five‐year lung cancer survival

Cited by 138 publications

References 50 publications

Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling

Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling

Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer

A novel in silico reverse-transcriptomics-based identification and blood-based validation of a panel of sub-type specific biomarkers in lung cancer

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