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The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma

Oncogene volume 39, pages 2103–2117 (2020)Cite this article

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Abstract

Rational new strategies are needed to treat tumors resistant to kinase inhibitors. Mechanistic studies of resistance provide fertile ground for development of new approaches. Cancer drug addiction is a paradoxical resistance phenomenon, well-described in MEK-ERK-driven solid tumors, in which drug-target overexpression promotes resistance but a toxic overdose of signaling if the inhibitor is withdrawn. This can permit prolonged control of tumors through intermittent dosing. We and others showed previously that cancer drug addiction arises also in the hematologic malignancy ALK-positive anaplastic large-cell lymphoma (ALCL) resistant to ALK-specific tyrosine kinase inhibitors (TKIs). This is driven by the overexpression of the fusion kinase NPM1-ALK, but the mechanism by which ALK overactivity drives toxicity upon TKI withdrawal remained obscure. Here we reveal the mechanism of ALK-TKI addiction in ALCL. We interrogated the well-described mechanism of MEK/ERK pathway inhibitor addiction in solid tumors and found it does not apply to ALCL. Instead, phosphoproteomics and confirmatory functional studies revealed that the STAT1 overactivation is the key mechanism of ALK-TKI addiction in ALCL. The withdrawal of TKI from addicted tumors in vitro and in vivo leads to overwhelming phospho-STAT1 activation, turning on its tumor-suppressive gene-expression program and turning off STAT3’s oncogenic program. Moreover, a novel NPM1-ALK-positive ALCL PDX model showed a significant survival benefit from intermittent compared with continuous TKI dosing. In sum, we reveal for the first time the mechanism of cancer drug addiction in ALK-positive ALCL and the benefit of scheduled intermittent dosing in high-risk patient-derived tumors in vivo.

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Fig. 1: Co-selection for resistance and drug addiction by lorlatinib in ALK-positive ALCL.
Fig. 2: ALK’s canonical downstream pathways do not mediate overdose signaling.
Fig. 3: Phosphoproteomics yields candidate drivers of NPM1-ALK overdose-driven toxicity.
Fig. 4: STAT1 activation drives NPM1-ALK overdose-mediated cell death.
Fig. 5: Antitumor activity and STAT1 activation by IFNγ in vitro.
Fig. 6: TKI resistance and intermittent dosing in an ALK-positive ALCL PDX model.

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Code availability

All codes were run on the open-source programming environment R (version 3.3.1). The area under the curve was analyzed using the equation mentioned previously and the open-source package “AUC”. The RNA-Seq was visualized as a heatmap using the open-source built-in package “heatmap”.

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Acknowledgements

This work was supported by a grant from National Institutes of Health/National Cancer Institute, 1R01CA190696-01 (JHS) and 5R01CA190696-05. We would also like to acknowledge the Sheila and David Fuente Graduate Program in Cancer Biology at University of Miami. SSR is a PhD candidate at University of Miami. This work is submitted in partial fulfillment of the requirement of the PhD. We would also like to thank Dr Izidore Lossos, University of Miami, for his input and suggestions in writing the manuscript.

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Authors and Affiliations

  1. Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    Soumya S. Rajan & Artavazd Arumov

  2. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Soumya S. Rajan, Amit Dipak Amin, Lingxiao Li, Deukwoo Kwon, Mercedes F. Kweh, Artavazd Arumov, Evan R. Roberts, Aimin Yan, Xi Steven Chen, Daniel Bilbao & Jonathan H. Schatz

  3. Division of Hematology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA

    Amit Dipak Amin, Lingxiao Li, Mercedes F. Kweh & Jonathan H. Schatz

  4. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Delphine C. Rolland, Kojo S. J. Elenitoba-Johnson & Megan S. Lim

  5. Department of Biosystems Engineering, University of Arizona, Tucson, AZ, USA

    Haiquan Li

  6. Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

    Deukwoo Kwon & Xi Steven Chen

  7. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Venkatesha Basrur

  8. Department of Medicine, Bio5 Institute, UA Cancer Center, Ann Arbor, MI, USA

    Soham D. Puvvada & Yves A. Lussier

  9. Interdisciplinary Program in Statistics, University of Arizona, Tucson, AZ, USA

    Yves A. Lussier

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Rajan, S.S., Amin, A.D., Li, L. et al. The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma. Oncogene 39, 2103–2117 (2020). https://doi.org/10.1038/s41388-019-1136-4

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