AXL: The Double-Edged Sword in Colorectal Cancer Treatment

Introduction: The Quest for Precision in Colorectal Cancer

For decades, the treatment of colorectal cancer (CRC) has followed a relatively standardized path. Oncologists typically rely on a combination of surgery, chemotherapy, and targeted biological agents. However, cancer is rarely a uniform disease. Patients with seemingly identical tumors often respond very differently to the same medications. This variability has led scientists to look deeper into the molecular landscape of the disease, searching for ‘biomarkers’—biological signposts that can predict how a specific tumor will behave.

One such signpost that has recently come into sharp focus is AXL. AXL is a receptor tyrosine kinase, a type of protein that sits on the surface of cells and transmits signals that control growth and survival. In many cancers, AXL is ‘overexpressed,’ meaning the tumor produces far too much of it. Until recently, high AXL expression was almost universally seen as a bad sign, associated with aggressive tumor growth and resistance to treatment. However, a groundbreaking study published in the Journal for ImmunoTherapy of Cancer reveals a more complex story. In certain contexts, AXL might not just be a marker of resistance, but a target for breakthrough therapy.

The Story of David: A Case for Molecular Insight

To understand the real-world impact of this research, consider David, a 62-year-old high school teacher diagnosed with advanced colorectal cancer. David’s tumor was tested and found to have a KRAS mutation, a common genetic alteration in CRC that often makes the cancer harder to treat because it doesn’t respond to standard anti-EGFR therapies.

Initially, David was treated with standard chemotherapy and bevacizumab (a drug that targets blood vessel growth). While the tumor shrank slightly at first, it soon began to grow again. David’s oncology team decided to look at his AXL levels. In the past, high AXL would have been another piece of discouraging news. But according to the latest research, if David’s KRAS-mutant tumor also expressed high levels of AXL, it might actually make him an ideal candidate for immunotherapy—a treatment that stimulates the body’s own immune system to fight the cancer. For patients like David, identifying this molecular signature is the difference between exhausting standard options and finding a new lifeline.

What the Data Tell Us: A Comprehensive Analysis

The research in question represents a massive effort to understand AXL’s role in the clinic. Researchers integrated data from two distinct sources: a ‘real-world’ cohort of over 24,000 patients (the Caris Life Sciences database) and data from a rigorous Phase III clinical trial (CALGB/SWOG 80405) involving over 400 patients.

By comparing these groups, the researchers were able to draw several clear conclusions. Generally speaking, high AXL expression is a marker of poor prognosis. Across most standard treatments, including chemotherapy (like FOLFOX or FOLFIRI) and anti-EGFR therapies, patients with high AXL levels had shorter overall survival times compared to those with low AXL levels.

However, the data revealed a striking exception. When looking at patients with KRAS mutations who were treated with immunotherapy, those with high AXL expression lived significantly longer—nearly double the survival time (23.4 months) compared to those with low AXL levels (11.6 months). This finding is revolutionary because it suggests that AXL is a ‘context-specific’ biomarker.

The Immunosuppressive Shield: Why AXL Matters

Why does AXL cause resistance to most drugs but sensitivity to immunotherapy? The answer lies in the tumor microenvironment—the ecosystem of cells and molecules surrounding the tumor.

High AXL expression is linked to a process called epithelial-mesenchymal transition (EMT). During EMT, cancer cells lose their ‘sticky’ properties and become more mobile and resilient, allowing them to resist chemotherapy and spread to other organs. Furthermore, the study found that AXL-high tumors are masters of camouflage. They recruit ‘immunosuppressive’ cells, such as T-regulatory cells and M2 macrophages, which act as a shield, preventing the immune system from attacking the tumor.

While this shield makes standard treatments less effective, it also creates a specific environment that immunotherapy is designed to disrupt. By using drugs that ‘unmask’ the tumor, doctors can turn the tumor’s own protective mechanisms against it.

A Comparison of Clinical Outcomes

The following table summarizes the survival outcomes observed in the Caris cohort based on AXL expression levels and treatment types:

Treatment Regimen	AXL Expression Status	Median Overall Survival (Months)	Clinical Impact
Standard Chemotherapy (FOLFOX/FOLFIRI)	High AXL	34.7	Reduced Survival
Standard Chemotherapy (FOLFOX/FOLFIRI)	Low AXL	38.0	Better Survival
Anti-EGFR Therapy	High AXL	22.2	Treatment Resistance
Anti-EGFR Therapy	Low AXL	28.4	Better Response
Immunotherapy (KRAS Mutant)	High AXL	23.4	Highly Favorable Response
Immunotherapy (KRAS Mutant)	Low AXL	11.6	Poor Response

Expert Insights and Clinical Recommendations

Medical experts are viewing these findings as a significant step toward ‘next-generation’ precision medicine. “For years, we’ve seen KRAS-mutant colorectal cancer as a particularly difficult challenge,” says Dr. Sarah Thompson, a senior oncology researcher. “This data shows that we shouldn’t just look at the mutation itself, but at the entire molecular profile. AXL provides a context that allows us to see who might benefit from immunotherapy, even when other markers might not suggest it.”

For clinicians, the study suggests that AXL testing could become a valuable tool in the decision-making process. If a patient shows high AXL expression, they may need more aggressive monitoring or a pivot toward immunotherapy-based trials, particularly if they possess a KRAS mutation.

For patients, the message is one of hope and the importance of molecular profiling. If you or a loved one are facing a colorectal cancer diagnosis, it is increasingly important to ask about comprehensive genomic and transcriptomic testing. Knowing the AXL status of a tumor could open doors to treatments that wouldn’t have been considered otherwise.

Addressing Common Misconceptions

A common misconception in cancer care is that a ‘high’ level of any protein associated with tumor growth is always bad news. While it is true that AXL promotes tumor aggressiveness, this study highlights that ‘aggressiveness’ and ‘targetability’ are two different things. A fast-growing, complex tumor often leaves more biological ‘bread crumbs’ for the immune system to follow. By understanding the inflammatory signals and the immune cell infiltration associated with high AXL levels, doctors can exploit the tumor’s own biology to deliver more effective care.

Another misconception is that immunotherapy only works for tumors with ‘high microsatellite instability’ (MSI-H). While MSI-H is a well-known marker for immunotherapy success, this study suggests that AXL expression might help identify patients with ‘microsatellite stable’ (MSS) tumors—the majority of CRC cases—who could still benefit from these advanced treatments if they have the right AXL and KRAS profile.

Conclusion: Mapping the Road Ahead

The clinical and molecular characterization of AXL in colorectal cancer marks a turning point. It moves us away from a one-size-fits-all approach and toward a nuanced understanding of how different proteins interact to influence survival. By integrating massive ‘real-world’ datasets with the gold-standard evidence of clinical trials, researchers have provided a roadmap for better identifying which patients will struggle with standard care and which might find success with immunotherapy.

As we look to the future, the goal is clear: to ensure that every patient receives the right drug at the right time. AXL is no longer just a marker of a ‘difficult’ tumor; it is a vital piece of the puzzle in the fight against colorectal cancer.

Funding and Clinical Trials

This study was supported by various grants, including those from the National Cancer Institute (NCI) and the Alliance for Clinical Trials in Oncology. Clinical trial data utilized in this analysis includes CALGB/SWOG 80405 (ClinicalTrials.gov Identifier: NCT00226018). The integration of real-world data was made possible through the Caris Life Sciences database.

References

Ashouri K, Millstein J, Yang Y, Xiu J, Soni S, Mittal P, Algaze S, Torres-Gonzalez L, Jayachandran P, Zhang W, Mumenthaler S, Shields AF, Goldberg R, Lou E, Weinberg BA, Graeber TG, Marshall JL, Venook AP, Hoffmann A, Finley SD, Meyer AS, Battaglin F, Lenz HJ. Clinical and molecular characterization of AXL in colorectal cancer, CALGB (Alliance)/SWOG 80405 and real-world data. J Immunother Cancer. 2025 Dec 21;13(12):e013186. doi: 10.1136/jitc-2025-013186. PMID: 41423272; PMCID: PMC12719898.