Supplementary Video 1 from Crizotinib Inhibits Metabolic Inactivation of Gemcitabine in c-Met–driven Pancreatic Carcinoma
Amir AvanViola CarettiNiccola FunelElena GalvaniMina MaftouhRichard J. HoneywellTonny LagerweijOlaf van TellingenDaniela CampaniDieter FuchsHenk M.W. VerheulGerrit‐Jan SchuurhuisUgo BoggiGodefridus J. PetersThomas WürdingerElisa Giovannetti
0
Citation
0
Reference
10
Related Paper
Abstract:
<p>GIF file - 2361K, High-frequency ultrasound.</p>Keywords:
Pancreatic carcinoma
Cite
Citations (145)
Abstract 957: The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer
Abstract Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the ALK tyrosine kinase inhibitor (TKI) crizotinib. However, these cancers invariably relapse due to the development of resistance, and approximately 1/3 of such cancers develop resistance mutations within the ALK tyrosine kinase domain. Here we report the preclinical evaluation of the next-generation ALK TKI, LDK378 in the setting of crizotinib resistance. Using EML4-ALK mutant Ba/F3 cellular models, in vivo models of acquired resistance to crizotinib, and novel cell lines established from biopsies of crizotinib-resistant NSCLC patients, we have examined the efficacy of LDK378 in crizotinib-naïve and -resistant ALK-positive cancers. These studies reveal that LDK378 is more potent than crizotinib and effectively overcomes resistance in vitro and in vivo. In particular, LDK378 inhibits ALK harboring crizotinib resistance mutations, including L1196M, G1269A, I1171T and S1206Y. Cell lines derived from crizotinib-resistant biopsies were sensitive to LDK378, including one that did not harbor an ALK resistance mutation and was also sensitive to crizotinib, suggesting that some crizotinib-resistant cancers with wildtype ALK are still sensitive to complete ALK inhibition. We observed that LDK378 did not effectively overcome two crizotinib-resistant ALK mutations, G1202R and F1174C ALK, and mutations in one of these residues was identified in 5 out of 11 biopsies from patients with acquired resistance to LDK378. Altogether our results demonstrate that LDK378 can overcome many mechanisms of crizotinib resistance, consistent with emerging clinical data showing marked efficacy of LDK378 in patients with crizotinib-resistant disease. Citation Format: Luc Friboulet, Nanxin Li, Ryohei Katayama, Christian C. Lee, Justin F. Gainor, Adam S. Crystal, Pierre-Yves Michellys, Mark M. Awad, Noriko Yanagitani, Sungjoon Kim, AnneMarie Pferdekamper, Jie Li, Shailaja Kasibhatla, Frank Sun, Xiuying Sun, Su Hua, Peter McNamara, Sidra Mahmood, Elizabeth L. Lockerman, Naoya Fujita, Makoto Nishio, Jennifer L. Harris, Alice T. Shaw, Jeffrey A. Engelman. The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 957. doi:10.1158/1538-7445.AM2014-957
ALK inhibitor
Cite
Citations (2)
Objective To study the relationship between chemoresistance and the expression of survivin,induced by gemcitabine,in pancreatic carcinoma cell line PANC-1.Methods The pancreatic carcinoma cell line PANC-1 was cultured by RPMI 1640 and gemcitabine with the concentration of 1 μg /ml and 10 μg /mL respectively,and survivin expression was examined by RT-PCR and Western blot.The relationship of the survivin level of the cell and its chemoresistance to gemcitabine was analyzed.Results Tweenty-four and 48 hours after culture with gemcitabine concentration of 1 μg /ml and 10 μg /mL respectively,survivinmRNA level was increased(1.34±0.12),(2.40±0.17),and(3.33±0.20),(4.41±0.18) folds,and the protein expression was enhanced(1.20±0.07),(1.48±0.19),and(2.90±0.04),(4.50±0.20) folds respectively.There was a significant difference between the two groups(P0.05).Conclusions The intensity of pancreatic carcinoma cell lines chemoresistance could be enhanced by the action of gemcitabine on the up-regulated expression of survivin.
Survivin
Pancreatic carcinoma
Cite
Citations (0)
Lung cancer is the leading cause of cancer-related death. NSCLC accounts for 80-90% of cases. In younger patients, adenocarcinoma is the most frequent histotype and 3-7% expresses the rearrange-ment of ALK oncogene, sensitive to TKIs. Crizotinib is the first ALK inhibitor approved by FDA. We present the case of a 17-year-old male with metastatic naïve ALK-positive adenocarcinoma, treated with crizotinib. He received crizotinib and obtained a prolonged response with PFS of 33 months. Crizotinib can be extremely effective in adolescent with naïve ALK-positive NSCLC but it hardly penetrates blood-brain barrier. Resistance mechanisms will be investigated for a better man-agement.
ALK inhibitor
Cite
Citations (0)
Cite
Citations (5)
We report on the case of a patient affected by advanced non-small cell lung cancer (NSCLC) harboring an anaplastic lymphoma kinase (ALK) gene rearrangement who did not respond to crizotinib but subsequently benefited from treatment with ceritinib (LDK378). Although second-generation ALK inhibitors have shown activity in patients pretreated with crizotinib who experienced secondary resistance, this is the first report to date describing their efficacy in a case of primary resistance. Of note, none of the previously described molecular mechanisms explaining resistance to crizotinib was detected on either the initial or post-crizotinib biopsies. We hypothesize that crizotinib was powerless in controlling disease progression due to its inadequate inhibition of ALK signaling. Although we lack any molecular evidence elucidating the primary crizotinib resistance, we believe that ceritinib treatment led to tumor regression thanks to its superior biological potency.
Ceritinib
ALK inhibitor
Gene rearrangement
Cite
Citations (8)
Cite
Citations (44)
New agents with high anti-tumor effects have been developed since 1990. Monotherapy with one of these agents, gemcitabine, was confirmed to be as effective as the standard chemotherapy regimen against NSCLC, and to have a lower toxicity profile. In addition, the combination of gemcitabine plus cisplatin can be expected to show a survival advantage. The combination therapy consisting of these two new anti-cancer agents is expected to show effectiveness equal to that of platinum-based combination chemotherapy. Gemcitabine is well tolerated, so that it can be a useful treatment for maintaining QOL among the elderly or in poor performance status patients with NSCLC. Considering that this agent is also effective against pancreatic cancer, further investigation for efficacy against other cancers is warranted.
Regimen
Combination chemotherapy
Cite
Citations (0)
ROS1 rearrangement acts as a driver mutation in 1-2% of NSCLC. Crizotinib is approved in this situation both in treatment naïve and pre-treated patients. Here we report our experience with crizotinib in patients with advanced NSCLC harbouring ROS1 rearrangement. Eleven patients were included in our study. More than half of our patients had associated comorbidities and one fourth of them had a compromised performance status. Out of 11 patients, 5 of them were exposed to crizotinib .The response rates among crizotinib treated patients was 80%. With a median follow up of 9 months, median PFS and OS were 5.4 months and 8.5 months respectively for the entire population. Analyzing the outcomes separately , median PFS and OS was not reached for those who received crizotinib compared to median PFS of 2.5 months and median OS of 4.2 months in those who were not exposed to crizotinib. The difference was statistically significant. Estimated 1 year OS was 80% for those who received crizotinib compared to 18% for who did not receive crizotinib. In conclusion, crizotinib is effective with acceptable side effect profile in patients with ROS1 rearranged NSCLC in our population.
Cite
Citations (8)
The treatment of advanced non-small cell lung cancer (NSCLC) has dramatically changed over the last decade. It has developed from an unspecific approach based on platinum doublet chemotherapy to a personalized, molecularly targeted therapy. Crizotinib is a new tyrosine kinase inhibitor approved for the treatment of NSCLC with gene rearrangement of EML4 and ALK. Despite good initial responses, patients treated with crizotinib relapse after an average of 10 months. In this case report, we present a patient with acquired crizotinib resistance whose adenocarcinoma responded to a second course of crizotinib following a drug holiday and chemotherapy with pemetrexed. This is the second case report to suggest that retreatment with crizotinib is an option for patients with initial benefit from ALK inhibition.
ALK inhibitor
Pemetrexed
Acquired resistance
Cite
Citations (13)