# The role of RNA splicing in non-small cell lung cancer

> **NIH VA I01** · JAMES A. HALEY VA MEDICAL CENTER · 2020 · —

## Abstract

Today, lung cancer is the leading cause of death in both men and women in industrialized
countries, accounting for an estimated 28% of all cancer deaths in the United States. Non-small cell lung
cancers (NSCLC) represent the majority of lung cancers and carry a poor prognosis with a median survival of
less than 12 months. Most patients present with unresectable disease, and the current treatment options of
chemotherapy and radiation are palliative at best. Therefore, new strategies are needed in the treatment of
NSCLC in order to impact this disease. In this regard, we are focusing on NSCLC models for examining distal
signaling mechanisms that modulate the generation and maintenance of NSCLC cells/tumors. Specifically, this
grant application begins with a focus on the consequence of expressing caspase 9b (C9b) in lung epithelium.
The expression of C9b is regulated by alternative RNA splicing via the inclusion or exclusion of a four exon
cassette (exons 3,4,5,6). Inclusion of this exon cassette into the mature transcript produces the pro-apoptotic
caspase 9 (caspase 9a) while the exclusion produces the anti-apoptotic and survival/oncogenic signaling factor,
caspase 9b. Studies from our laboratory have demonstrated that NSCLC tumors present with a dysregulated
(e.g. low) ratio of caspase 9/caspase 9b analogous to an anti-apoptotic/chemotherapy resistance phenotype.
Subsequent studies by our laboratory demonstrated that the expression of C9b had important functions in the
anchorage-independent growth (AIG) of NSCLC cells, AIG induced by oncogenic mutation in non-transformed
human bronchial epithelial cells, and chemotherapy sensitivity (e.g. cisplatinum and paclitaxel). Mechanistically,
our laboratory identified an exonic splicing silencer (C9/E3-ESS) in exon 3 that regulates the inclusion of the
exon 3,4,5,6 cassette of caspase 9 pre-mRNA. The RNA trans-factor, hnRNP L, was shown to associate with
this RNA cis-element, repress the inclusion of the exon cassette, and induce caspase 9b expression.
Importantly, phosphorylation of hnRNP L on ser52 (observed only in transformed cells) was required for
repression of the exon 3,4,5,6 cassette. Lastly, ser52 phosphorylation of hnRNP L was shown as a required
mediator of the tumorigenic capacity of NSCLC cells via the alternative splicing of caspase 9. These key
mechanisms are specific to transformed cells, translatable to >70% of NSCLCs, and at an extreme distal point
in oncogenic pathways. Therefore, these distal mechanisms are plausible and highly desired targets for the
development of new anti-cancer therapeutics. Our proposed studies will dramatically extend these previous
findings by first determining whether C9b is a key oncogenic signaling factor in the transformation of lung
epithelial cells. The next set of proposed studies will determine how hnRNP L becomes activated to drive the
expression of C9b.
 Our last set of proposed studies extend the role of hnRNP L in regard to NSCLC. In stark contrast ...

## Key facts

- **NIH application ID:** 9864001
- **Project number:** 5I01BX001792-08
- **Recipient organization:** JAMES A. HALEY VA MEDICAL CENTER
- **Principal Investigator:** CHARLES E. CHALFANT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864001

## Citation

> US National Institutes of Health, RePORTER application 9864001, The role of RNA splicing in non-small cell lung cancer (5I01BX001792-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9864001. Licensed CC0.

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