# Optimizing biologically-based rational polytherapy in ALK+ lung cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $362,569

## Abstract

Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) the
predominant histologic subtype of lung cancer and lung adenocarcinoma the major subset of NSCLC. Despite
recent clinical progress with the use of specific targeted therapies, drug resistance remains a problem that
limits patient survival. A promising strategy to combat cancer drug resistance is to deploy rational upfront
polytherapies that suppress the survival and emergence of resistant tumor cells. However, in most tumors with
oncogenic receptor kinases, the optimal initial polytherapy strategy is unclear because receptor kinases
typically engage multiple effector pathways, and which of these individual pathways, if any, is most critical to
tumor cell survival is poorly defined. We recently demonstrated in models of NSCLC harboring the recurrent
oncogenic ALK receptor kinase fusion (EML4-ALK or ALK+) that the RAS-MAPK pathway, but not other known
ALK effectors, is required for tumor cell survival. We revealed that EML4-ALK drives RAS-MAPK signaling by
engaging all three major RAS isoforms (H, N-, K-RAS) via the HELP domain of EML4. MAPK pathway
reactivation via either genomic amplification of KRASWT (wild-type) or downregulation of the MAPK
phosphatase DUSP6 promoted resistance to ALK inhibition. Accordingly, upfront ALK and MEK co-inhibition
enhanced both the magnitude and duration of initial response in EML4-ALK NSCLC in vitro and in vivo models.
Furthermore, genomic amplification (or gene duplication) of KRASWT or downregulation of DUSP6 was
observed in ALK+ lung adenocarcinoma patients with acquired ALK inhibitor resistance. Together, our findings
provided new insight into the function of RAS-MAPK signaling in EML4-ALK NSCLC and the rationale for
upfront ALK + MEK inhibitor co-treatment to improve patient outcomes, a novel clinical trial we are leading.
Moreover, the findings indicated an unanticipated role of the EML4 partner in EML4-ALK oncogene function
and RAS signaling. Here, we will further extend our initial discovery to test the overall hypothesis that RAS
activation and signaling is a hallmark of oncogenic ALK function in NSCLC. In Aim 1, we will define the
biological basis of RAS-MAPK signaling and dependence in EML4-ALK NSCLC, dissecting the molecular and
cell biological control mechanisms governing RAS activation and signaling in ALK+ tumors. In Aim 2, we will
define the mechanism(s) that may limit curative response to ALK + MEK inhibitor polytherapy in ALK+ NSCLC
patients, levering cutting-edge CRISPR-based genetic screening studies and patient tumor samples from our
ALK + MEK inhibitor clinical trial. Overall, these multi-disciplinary, collaborative, patient-focused studies
spanning biochemical, genetic, pharmacologic, cell biological, and patient cohort and tumor molecular analysis
will provide fundamental insight into the function and control of RAS and oncogenic ALK signaling in cancer
and further enhance our novel ra...

## Key facts

- **NIH application ID:** 10078855
- **Project number:** 5R01CA211052-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Trever G Bivona
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,569
- **Award type:** 5
- **Project period:** 2017-01-11 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078855

## Citation

> US National Institutes of Health, RePORTER application 10078855, Optimizing biologically-based rational polytherapy in ALK+ lung cancer (5R01CA211052-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10078855. Licensed CC0.

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