What is chronic lymphocytic leukemia (CLL)?

Chronic lymphocytic leukemia (CLL) is a cancer where mature B lymphocytes accumulate in the body, often in lymphoid organs. This buildup leads to the development of the disease. Some patients experience slow progression, while others have an aggressive, chemotherapy-resistant form. Understanding CLL's characteristics is vital for developing effective treatments.

What is the role of mTORC2 in the context of CLL?

mTORC2 is a part of the mechanistic target of rapamycin (mTOR) signaling cascade. The study highlights the importance of inhibiting mTORC2 because it keeps the FOXO1 protein inactive. In CLL cells, the activity of mTORC2-AKT signaling keeps FOXO1 from working. The inhibition of mTORC2 reduces AKT-mediated signals which leads to reactivating FOXO1. This reactivation is key to prompting cancer cell death and reversing the cell survival mechanisms in CLL.

What is the significance of FOXO1 in CLL, and how is it affected?

The FOXO1 protein functions as a tumor suppressor. In CLL, cancer cells prevent FOXO1 from working properly, often by keeping it in the cytoplasm. Researchers found that by inhibiting mTORC2, FOXO1 function can be restored, leading to cancer cell death. High levels of FOXO1 gene expression in CLL cells are associated with a poorer prognosis, suggesting progressive disease. Reactivating FOXO1 is thus crucial for controlling CLL progression.

Why are combination therapies important for CLL treatment?

Combination therapies, such as AZD8055 with ibrutinib, have shown promise in treating CLL. The combined approach enhances FOXO1 activity, leading to better outcomes. This suggests that using drugs that target mTOR signaling pathways, combined with other targeted drugs, can improve how CLL is treated. These combination therapies are particularly relevant for patients with aggressive forms of the disease, potentially offering a more effective treatment strategy compared to traditional chemotherapy.

Illustration of FOXO1 protein activating cancer cell death by overcoming mTOR pathway obstacles.

Decoding CLL: How to Outsmart Cancer Cell Survival

Q: What is the role of AZD8055 in the treatment of CLL?

AZD8055 is a dual mTORC1/2 inhibitor used in the research. The study showed that AZD8055 effectively reduced CLL cell survival, especially in high-risk patients. Combining AZD8055 with ibrutinib, a BTK inhibitor, further enhanced FOXO1 activity, indicating a promising strategy for CLL treatment. The use of AZD8055 in mice models also showed a significant reduction in tumor burden, supporting the potential of mTOR inhibition as a treatment.

Soraya Malik in Health & Wellness December 2025 • 4 min read.

"New research reveals how inhibiting specific pathways can reactivate tumor suppression, offering hope for chronic lymphocytic leukemia treatment."

Chronic lymphocytic leukemia (CLL) is a type of cancer characterized by the accumulation of mature B lymphocytes in the body. The cells infiltrate and gather in lymphoid organs. While some patients with CLL experience a slow, manageable progression, others face a highly aggressive form of the disease resistant to typical chemotherapy treatments.

Scientists are focusing on identifying prognostic markers and creating novel therapeutic strategies. B-cell receptor (BCR) signaling is critical for CLL progression. When BCR is activated, it triggers a cascade of events that allow leukemic cells to survive. Interrupting these signals is key to controlling disease progression.

Recent studies show that targeting the mechanistic target of rapamycin (mTOR) signaling cascade, is a new way to treat CLL. Researchers found that dual mTORC1/2 inhibitors are effective in reducing cancer cell viability. This approach reactivates a tumor-suppressing pathway controlled by the FOXO1 protein. Combination therapies show promise in fighting CLL, especially when used with other targeted drugs.

Unlocking FOXO1: The Key to CLL Cell Death

Illustration of FOXO1 protein activating cancer cell death by overcoming mTOR pathway obstacles.

Researchers investigated how to restore FOXO1 function in CLL cells, since mTORC2-AKT activity keeps FOXO1 inactive. By inhibiting mTORC2, scientists aimed to reactivate FOXO1, prompting cancer cell death. They treated CLL cells with AZD8055, a dual mTORC1/2 inhibitor. The results showed that AZD8055 effectively reduced CLL cell survival, particularly in high-risk patients. Combining AZD8055 with ibrutinib, a BTK inhibitor, further enhanced FOXO1 activity.

The study showed that in CLL cells isolated from patient samples, FOXO1 gene expression was higher in subsets that had a poorer prognosis. High levels of FOXO1 indicates progressive disease. Further investigation revealed that the cancer cells prevent FOXO1 from working by sequestering it in the cytoplasm, a region of the cell outside the nucleus, through phosphorylation.

The researchers found that:

Dual mTORC1/2 inhibition reactivates FOXO1 function in CLL cells.
AZD8055 treatment reduces cancer cell survival, especially in high-risk CLL subsets.
mTORC2 inhibition decreases AKT-mediated signals, reactivating FOXO1.
Combination of AZD8055 with ibrutinib enhances FOXO1 activity, showing potential for future CLL therapies.

The team also used mice to test the effects of mTOR inhibition on CLL. The mice treated with AZD8055 had a significant reduction in tumor burden, showing that mTORC1/2 inhibition is effective in controlling CLL progression. The results suggest that drugs targeting mTOR signaling pathways, alone or in combination with other treatments, may change how CLL is treated, particularly for patients with aggressive forms of the disease.

A New Horizon for CLL Treatment

This research highlights the potential of dual mTOR inhibitors, like AZD8055, in treating CLL, and how to reverse cell survival mechanisms and reactivate tumor suppressor activity. The team demonstrated that by inhibiting mTORC2, FOXO1 can be reactivated, prompting cancer cell death.

Combination therapies are a way to prevent drug resistance. The authors found combining AZD8055 with ibrutinib had a greater anti-cancer effect than either drug alone, reducing the tumor load. Combining different therapies may improve clinical responses and reduce the risk of relapse.

Targeting mTOR and related pathways may offer the opportunity to improve treatment, especially for high-risk patients. While more studies are needed, this research provides hope for patients and highlights new paths for future CLL therapies.