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

Soumya S. Rajan, Amit Dipak Amin, Lingxiao Li, Delphine C. Rolland, Haiquan Li, Deukwoo Kwon, Mercedes F. Kweh, Artavazd Arumov, Evan R. Roberts, Aimin Yan, Venkatesha Basrur, Kojo S.J. Elenitoba-Johnson, Xi Steven Chen, Soham D. Puvvada, Yves A. Lussier, Daniel Bilbao, Megan S. Lim, Jonathan H. Schatz

Research output: Contribution to journalArticle

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tumors, in which drug-target overexpression promotes resistance but a toxic overdose of signaling if the inhibitor is withdrawn.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.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2019

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T-Cell Lymphoma
Substance-Related Disorders
Anaplastic Large-Cell Lymphoma
Protein-Tyrosine Kinases
Neoplasms
Phosphotransferases
MAP Kinase Signaling System
Poisons
Mitogen-Activated Protein Kinase Kinases
Hematologic Neoplasms
Gene Expression
Survival

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Rajan, S. S., Amin, A. D., Li, L., Rolland, D. C., Li, H., Kwon, D., ... Schatz, J. H. (Accepted/In press). The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma. Oncogene. https://doi.org/10.1038/s41388-019-1136-4

The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma. / Rajan, Soumya S.; Amin, Amit Dipak; Li, Lingxiao; Rolland, Delphine C.; Li, Haiquan; Kwon, Deukwoo; Kweh, Mercedes F.; Arumov, Artavazd; Roberts, Evan R.; Yan, Aimin; Basrur, Venkatesha; Elenitoba-Johnson, Kojo S.J.; Chen, Xi Steven; Puvvada, Soham D.; Lussier, Yves A.; Bilbao, Daniel; Lim, Megan S.; Schatz, Jonathan H.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

Rajan, SS, Amin, AD, Li, L, Rolland, DC, Li, H, Kwon, D, Kweh, MF, Arumov, A, Roberts, ER, Yan, A, Basrur, V, Elenitoba-Johnson, KSJ, Chen, XS, Puvvada, SD, Lussier, YA, Bilbao, D, Lim, MS & Schatz, JH 2019, 'The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma', Oncogene. https://doi.org/10.1038/s41388-019-1136-4
Rajan, Soumya S. ; Amin, Amit Dipak ; Li, Lingxiao ; Rolland, Delphine C. ; Li, Haiquan ; Kwon, Deukwoo ; Kweh, Mercedes F. ; Arumov, Artavazd ; Roberts, Evan R. ; Yan, Aimin ; Basrur, Venkatesha ; Elenitoba-Johnson, Kojo S.J. ; Chen, Xi Steven ; Puvvada, Soham D. ; Lussier, Yves A. ; Bilbao, Daniel ; Lim, Megan S. ; Schatz, Jonathan H. / The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma. In: Oncogene. 2019.
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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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AU - Rajan, Soumya S.

AU - Amin, Amit Dipak

AU - Li, Lingxiao

AU - Rolland, Delphine C.

AU - Li, Haiquan

AU - Kwon, Deukwoo

AU - Kweh, Mercedes F.

AU - Arumov, Artavazd

AU - Roberts, Evan R.

AU - Yan, Aimin

AU - Basrur, Venkatesha

AU - Elenitoba-Johnson, Kojo S.J.

AU - Chen, Xi Steven

AU - Puvvada, Soham D.

AU - Lussier, Yves A.

AU - Bilbao, Daniel

AU - Lim, Megan S.

AU - Schatz, Jonathan H.

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N2 - 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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