# Overcoming Resistance Mechanisms to Anaplastic Lymphoma Kinase Inhibitors

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $396,625

## Abstract

Project Summary
Non-small cell lung cancers (NSCLC) harboring oncogenic anaplastic lymphoma kinase (ALK) gene
rearrangements (i.e., ‘ALK+’) comprise a distinct molecular subset of lung cancer with marked sensitivity to ALK
tyrosine kinase inhibitors (TKIs). While ALK TKIs are initially highly effective, acquired drug resistance remains
a fundamental challenge that limits clinical benefit and causes disease relapse in most patients. We and others
have characterized mechanisms of resistance, in particular so-called “on-target” resistance mediated by
secondary acquired ALK kinase domain mutations that can be overcome with more potent next-generation (2nd-
or 3rd-generation) inhibitors. In recent years, the standard treatment paradigm for patients diagnosed with
advanced ALK+ lung cancers has shifted from sequential therapy using the 1st-generation ALK TKI crizotinib
followed by next-generation TKIs, to initial therapy using a next-generation ALK TKI upfront. Our preliminary data
indicate that off-target (i.e., ALK-independent) resistance mechanisms are prevalent following next-generation
ALK TKIs. Yet, the spectrum of off-target resistance mechanisms and strategies to overcome these remain
poorly understood, presenting a barrier to the development of treatment options for these patients. The
overarching objective of the proposed research is to identify and develop complementary, mechanism-informed
and mechanism-agnostic approaches for overcoming off-target resistance to next-generation ALK TKIs. We will
use comprehensive genomic and non-genomic assessment of an expanded cohort of patient tumor specimens
to determine the clinical spectrum of off-target resistance mechanisms after first-line use of next-generation ALK
TKIs, and we will develop new methods for identifying patients with bypass-mediated resistance most likely to
benefit from rationally designed combination therapies. Using ALK TKI-resistant tumor cell lines derived from
patient biopsies, we will screen for epigenetic mechanisms that drive resistance independent of canonical bypass
signaling pathways, with initial studies focused on defining the role of the transcriptional co-activator p300/CBP
as a novel driver of off-target ALK TKI resistance and therapeutic target. These efforts will enable patient-specific,
mechanism-informed therapeutic strategies. In parallel, we will develop a mechanism-agnostic approach that
leverages ALK as a tumor-specific “neoantigen” whose expression is maintained in resistant tumors. Using T
cell-based functional screens, we will identify ALK-reactive T cell receptors (TCRs) that are capable of
recognizing resistant ALK+ NSCLCs. This will provide the foundation for engineering ALK TCR adoptive cellular
therapy as a TKI-orthogonal, immune-based approach for overcoming resistance. Collectively, the proposed
studies will provide a comprehensive understanding of resistance to next-generation ALK TKIs and pave the way
for the development of new therapeutic strateg...

## Key facts

- **NIH application ID:** 10868541
- **Project number:** 5R01CA164273-12
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Aaron N Hata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,625
- **Award type:** 5
- **Project period:** 2012-02-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868541

## Citation

> US National Institutes of Health, RePORTER application 10868541, Overcoming Resistance Mechanisms to Anaplastic Lymphoma Kinase Inhibitors (5R01CA164273-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10868541. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*