Evidence suggesting that discontinuous dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors

Amit Dipak Amin, Soumya S. Rajan, Winnie S. Liang, Praechompoo Pongtornpipat, Matthew J. Groysman, Edgar O. Tapia, Tara L. Peters, Lori Cuyugan, Jonathan Adkins, Lisa M. Rimsza, Yves A. Lussier, Soham D. Puvvada, Jonathan H Schatz

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The anaplastic lymphoma kinase (ALK) is chromosomally rearranged in a subset of certain cancers, including 2% to 7% of non-small cell lung cancers (NSCLC) and ∼70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK+ NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to ∼ 10 months. Kinase domain mutations are detectable in 25% to 37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug-resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications.

Original languageEnglish (US)
Pages (from-to)2916-2927
Number of pages12
JournalCancer Research
Volume75
Issue number14
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

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Phosphotransferases
Neoplasms
Anaplastic Large-Cell Lymphoma
Non-Small Cell Lung Carcinoma
Drug Resistance
Mutation
anaplastic lymphoma kinase
B-Lymphoid Precursor Cells
Poisons
Drug and Narcotic Control
Oncogene Proteins
Pharmaceutical Preparations
Disease-Free Survival
Cell Survival
Up-Regulation
Cytokines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Evidence suggesting that discontinuous dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors. / Amin, Amit Dipak; Rajan, Soumya S.; Liang, Winnie S.; Pongtornpipat, Praechompoo; Groysman, Matthew J.; Tapia, Edgar O.; Peters, Tara L.; Cuyugan, Lori; Adkins, Jonathan; Rimsza, Lisa M.; Lussier, Yves A.; Puvvada, Soham D.; Schatz, Jonathan H.

In: Cancer Research, Vol. 75, No. 14, 15.07.2015, p. 2916-2927.

Research output: Contribution to journalArticle

Amin, AD, Rajan, SS, Liang, WS, Pongtornpipat, P, Groysman, MJ, Tapia, EO, Peters, TL, Cuyugan, L, Adkins, J, Rimsza, LM, Lussier, YA, Puvvada, SD & Schatz, JH 2015, 'Evidence suggesting that discontinuous dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors', Cancer Research, vol. 75, no. 14, pp. 2916-2927. https://doi.org/10.1158/0008-5472.CAN-14-3437
Amin, Amit Dipak ; Rajan, Soumya S. ; Liang, Winnie S. ; Pongtornpipat, Praechompoo ; Groysman, Matthew J. ; Tapia, Edgar O. ; Peters, Tara L. ; Cuyugan, Lori ; Adkins, Jonathan ; Rimsza, Lisa M. ; Lussier, Yves A. ; Puvvada, Soham D. ; Schatz, Jonathan H. / Evidence suggesting that discontinuous dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors. In: Cancer Research. 2015 ; Vol. 75, No. 14. pp. 2916-2927.
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AU - Liang, Winnie S.

AU - Pongtornpipat, Praechompoo

AU - Groysman, Matthew J.

AU - Tapia, Edgar O.

AU - Peters, Tara L.

AU - Cuyugan, Lori

AU - Adkins, Jonathan

AU - Rimsza, Lisa M.

AU - Lussier, Yves A.

AU - Puvvada, Soham D.

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