# Hi-jacking the kynurenine pathway: A new path used by cisplatin resistant non-small cell lung cancer to survive and evade immune surveillance under high ROS

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2020 · —

## Abstract

The toll of lung cancer deaths in the United States exceeds that of the next four major cancers combined, and is
the most common cancer found in veterans. Not only is the incidence higher, but the survival is lower than in
civilian populations. Surgery is the main treatment for early stage lung cancer, but most patients already have
locally advanced or metastatic disease at the time of diagnosis. Subsequently, chemotherapy or combined
chemotherapy with radiation therapy remains the primary modality of treatment. Immunotherapy with check point
inhibitors (PD-1) has received much attention lately, offering a longer duration of response. However, the
response rate is still low in lung cancer. In fact, a recent report on these immunotherapy treatment did not show
improved efficacy over standard chemotherapy and failed as first line treatment in lung cancer. Therefore, the
majority of lung cancer patients still require traditional chemotherapeutic agents that affect proliferating cells such
as cisplatin or carboplatin for control of their disease. Despite early positive responses to platinum-based
chemotherapy, the majority of lung cancer patients develop drug resistance, and cisplatin resistance remains
the major obstacle for the effective treatment of lung cancer.
 For the past three decades, no drugs have reversed cisplatin resistance or selectively killed non-small
cell lung cancer cisplatin resistant (CR) cells. We discovered that CR cells possess higher basal level of reactive
oxygen species (ROS) and do not follow classic aerobic glycolysis (Warburg effect), but instead consume a
higher rate of glutamine and tryptophan. Consequently, the tumor microenvironment accommodates lower levels
of amino acids and becomes unfavorable for cytotoxic T-effector cells (T-eff) which are highly anabolic and also
require high amounts of nutrients to expand. With this understanding, we have discovered that CR cells activate
the kynurenine pathway (L-tryptophan catabolism) in order to cope with higher ROS concentrations during their
growth and proliferation, making this pathway essential for their survival. Importantly, L-kynurenine (KYN), a
product of the kynurenine pathway, plays a key role in reprogramming naïve T-cells to the immune suppressive
regulatory T-cell (T-reg) phenotype. Thus, creating an environment in which CR tumors are able to proliferate
and escape from the immune system.
 In this application, we plan to further confirm and exploit these crucial findings by: First; establishing how
the activated kynurenine pathway (KP) shields cisplatin resistant non-small cell lung cancer from immune
surveillance and enhances cisplatin resistance. Second; determining how metabolic reprogramming can lead to
alterations in the tumor microenvironment favoring immunosuppressive T-cells in CR tumors. Third; overcoming
cisplatin resistance by inhibiting KP. Fourth; identifying the population of lung cancer patients who will be benefit
greatly from the combination of...

## Key facts

- **NIH application ID:** 9932905
- **Project number:** 5I01BX004371-03
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** Medhi Wangpaichitr
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932905

## Citation

> US National Institutes of Health, RePORTER application 9932905, Hi-jacking the kynurenine pathway: A new path used by cisplatin resistant non-small cell lung cancer to survive and evade immune surveillance under high ROS (5I01BX004371-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932905. Licensed CC0.

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