# Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $420,375

## Abstract

ABSTRACT
A specific subset of T cell lymphoma (TCL) called Anaplastic Large Cell Lymphoma (ALCL) frequently harbors
chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene. Chemotherapy is the
current standard of care for ALK+ ALCL, but fails in approximately 30% of patients. Most ALK+ ALCL that fail
chemotherapy respond well to the ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, with higher
responses in children than in adults and FDA agency recently granted the breakthrough therapy designation
for crizotinib for the treatment of patients with relapsed/refractory ALK+ ALCL. Based on these exciting results,
it is not impossible to think that in the future ALK TKIs will become the first-line therapy for ALCL, thus
overcoming the long-term toxicity of chemotherapy. A similar switch has happened in the case of ALK+ non-
small cell lung cancer (NSCLC) that is currently treated in first-line with ALK TKIs.
Despite most ALK+ ALCL patients refractory to chemotherapy achieve complete remission when treated with
ALK TKIs, still a fraction of patients quickly develop resistance. In addition, responder patients are not
completely cured as discontinuation of crizotinib is associated with rapid lymphoma relapse even after many
years of complete remission with undetectable disease. Therefore, ALCL can develop molecular mechanisms
that protect lymphoma cells from the activity of ALK TKIs. To achieve the ambitious goal of treating ALK+
ALCL with targeted therapy and replace chemotherapy as much as possible, there is need to completely
understand these mechanisms that lead to ALK TKI resistance in ALCL.
By genetic screenings, extensive sequencing and mouse models, we identified three main mechanisms
leading to ALK TKI resistance and possibly sustaining the long-term persistence of ALCL cells: - we identified a
phosphatase-mediated mechanism when we discovered that PTPN1 and PTPN2 are phosphatases of ALK
and together with the SHP2 phosphatase regulate the sensitivity of ALCL cells to ALK TKIs; - we discovered
that activation of PI3Kγ signaling supports survival of persister cells during ALK inhibition; - we elucidated the
key role of the Rho family GTPases to mediate ALK signaling in ALCL. For this project, we hypothesize that
targeting these three main pathways with specific combined therapies could cope with resistance and lead to
the eradication of persister cells for a complete cure of ALK+ ALCL. In this project, we will validate this concept
with in vitro and in vivo models that will be used to test different therapeutic strategies. Thus, ALK+ ALCL could
become the first T cell lymphoma to be completely cured without chemotherapy, with obvious long-term
benefits for children and adults affected by this disease. In addition, our results could pave the way to broaden
these therapeutic concepts to other incurable TCL.

## Key facts

- **NIH application ID:** 10120058
- **Project number:** 2R01CA196703-06
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Roberto Chiarle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,375
- **Award type:** 2
- **Project period:** 2015-07-16 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120058

## Citation

> US National Institutes of Health, RePORTER application 10120058, Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma (2R01CA196703-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120058. Licensed CC0.

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