Illustration of lung cancer cells with INSL4 molecules on their surface.

Lung Cancer Breakthrough: Targeting INSL4 for LKB1-Deficient Tumors

Lena Kashyap in Health & Wellness December 2025 • 4 min read.

"New research reveals a promising therapeutic target for a particularly aggressive form of lung cancer."

Lung cancer remains a leading cause of cancer-related deaths worldwide, with non-small cell lung carcinoma (NSCLC) being the most prevalent type. While targeted therapies have revolutionized treatment for some lung cancer patients, those with LKB1-inactivated tumors still lack effective options. This is because LKB1-deficient lung cancers possess distinct biological characteristics, but targeted treatments are currently unavailable.

Now, a groundbreaking study offers hope. Researchers have uncovered a critical signaling pathway involving a protein called INSL4 that is essential for the survival and growth of LKB1-deficient lung cancer cells. This discovery opens the door to developing new therapies that specifically target this pathway.

This article will delve into the details of this research, explaining how INSL4 signaling works in LKB1-deficient lung cancers and why it represents a promising therapeutic target.

INSL4: The Key to LKB1-Deficient Lung Cancer Growth

Illustration of lung cancer cells with INSL4 molecules on their surface.

The research team began by analyzing gene expression in lung cancer cells to identify potential downstream targets of LKB1 inactivation. They discovered that INSL4, a member of the insulin/IGF/relaxin superfamily, was significantly overexpressed in LKB1-deficient NSCLC cells.

Further investigation revealed that LKB1 deficiency leads to increased activity of a transcription factor called CRTC-CREB, which in turn drives the overproduction of INSL4. This creates an autocrine signaling loop, where the cancer cells themselves produce INSL4, which then stimulates their own growth and survival.

INSL4 Overexpression: LKB1-deficient NSCLC cells showed significantly higher levels of INSL4 compared to normal cells.
Clinical Significance: Lung adenocarcinomas with high INSL4 expression were associated with advanced tumor stage, lymph node metastasis, and poorer survival rates.
Functional Role: Blocking INSL4 expression in LKB1-deficient lung cancer cells led to reduced growth and increased apoptosis (programmed cell death).

To confirm the importance of INSL4, the researchers blocked its expression in LKB1-deficient lung cancer cells both in vitro (in cell cultures) and in vivo (in mouse models). The results were striking: blocking INSL4 significantly reduced tumor growth and increased cancer cell death. Gene expression profiling revealed that INSL4 regulates genes involved in cell cycle progression, growth, and survival, offering additional insights into the mechanism of action.

A Promising New Target for Lung Cancer Therapy

This research provides compelling evidence that INSL4 signaling is a critical vulnerability in LKB1-deficient lung cancers. By identifying this pathway, scientists have opened up new possibilities for developing targeted therapies that can specifically disrupt INSL4 signaling and effectively treat this aggressive form of lung cancer.

While further research is needed to fully understand the intricacies of INSL4 signaling and develop effective INSL4-targeted therapies, this study represents a significant step forward in the fight against lung cancer.

Future efforts will focus on developing drugs that can block INSL4 activity or its interaction with its receptor, as well as exploring the potential of using INSL4 as a biomarker to identify patients who are most likely to benefit from such treatments. These findings offer renewed hope for improving the outcomes of patients with LKB1-deficient lung cancer.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1093/jnci/djy166, Alternate LINK

Title: Role Of Insl4 Signaling In Sustaining The Growth And Viability Of Lkb1-Inactivated Lung Cancer

Subject: Cancer Research

Journal: JNCI: Journal of the National Cancer Institute

Publisher: Oxford University Press (OUP)

Authors: Rongqiang Yang, Steven W Li, Zirong Chen, Xin Zhou, Wei Ni, Dongtao A Fu, Jianrong Lu, Frederic J Kaye, Lizi Wu

Published: 2018-11-13

Everything You Need To Know

What is LKB1-deficient lung cancer?

LKB1-deficient lung cancers are a particularly aggressive form of lung cancer, and they lack effective treatment options. This is because the LKB1-inactivated tumors possess distinct biological characteristics. Research has identified a novel signaling pathway, which is essential for the survival and growth of these cancer cells. This pathway involves the protein INSL4, which is overexpressed in these cells.

What is INSL4?

INSL4 stands for a member of the insulin/IGF/relaxin superfamily. It is a protein that is significantly overexpressed in LKB1-deficient NSCLC cells. The overexpression is due to the inactivation of LKB1, which leads to increased activity of a transcription factor called CRTC-CREB, which in turn drives the overproduction of INSL4, creating an autocrine signaling loop. Blocking INSL4 expression led to reduced growth and increased cancer cell death.

How is INSL4 related to LKB1?

The study found that LKB1 inactivation is directly linked to the overexpression of INSL4 in non-small cell lung carcinoma (NSCLC) cells. When LKB1 is deficient, it triggers a signaling cascade that leads to the increased production of INSL4. The elevated levels of INSL4 then promote the growth and survival of the cancer cells, which is why it is considered a promising therapeutic target.

Why is blocking INSL4 signaling important?

Blocking INSL4 signaling is significant because it can effectively target and disrupt the growth of LKB1-deficient lung cancer cells. This has been demonstrated through research in vitro (in cell cultures) and in vivo (in mouse models), where blocking INSL4 expression led to reduced tumor growth and increased cancer cell death (apoptosis). By targeting INSL4, scientists aim to develop new therapies that can specifically eliminate these aggressive cancer cells, offering new hope for patients.

What are the implications of this research?

The implications of this research are vast. It opens new avenues for developing targeted therapies specifically designed to disrupt the INSL4 signaling pathway in LKB1-deficient lung cancers. This could lead to more effective treatments for patients who currently lack effective options. Furthermore, understanding the mechanisms of INSL4 in these cancers could pave the way for earlier detection and more personalized treatment strategies, ultimately improving patient outcomes and survival rates.