Rewiring Cancer Cells: Turning Adaptability Into Vulnerability

Cancer cells must adapt to their environment, posing a hurdle for therapy development and leading to drug resistance. However, this flexibility could be manipulated for a new approach to cancer therapy.

Different cell states contribute to heterogeneity within tumors, which is critical to cancer progression and forms a hallmark of cancer.

Single-cell analyses have revealed distinct cancer cell states, identified gene expression programs commonly disrupted in cancer, and illustrated that certain cell states recur across cancer types. Tumor cells can also dynamically switch between states.

Epigenetic and signaling mechanisms contribute to changes in cancer cell state, enabling malignant cells to adapt, survive, and evade treatment. The nature of these changes indicates they may be reversible.

“Cell state plasticity enables cancer cells to adapt and explore phenotypic space, with cell states being highly dynamic and malleable,” Prof. Bart Vanhaesebroeck, leader of REWIRE-CAN—a team funded by Cancer Grand Challenges, told Technology Networks. 

REWIRE-CAN aims to reprogram cancer cells to manipulate their states and disadvantage the tumor, offering a different approach to cancer therapy.

Rewiring cancer cells to their disadvantage 

We have detailed knowledge of how cancer cells are wired, including how proliferation and survival signals are altered. By changing the wiring within cancer cells, it may be possible to steer them towards a less malignant state. 

“REWIRE-CAN proposes to use signaling and epigenetic modulators to regulate and steer these [cell state-altering] processes to ‘rewire’ cancer cells,” Vanhaesebroeck said. “Our approach will complement existing cancer therapies by identifying new drug combinations and developing novel approaches, such as pathway activators, to constrain cancer cells into drug-sensitive states.” 

The team’s approach is threefold: hyperactivating oncogenic signaling, forcing treatment-resistant cells to become sensitive, and creating “bottlenecks” to fix cells in a certain state.

Hyperactivating oncogenic signaling 

Cancer cells exist in a “Goldilocks” state—enough oncogenic signaling to rapidly grow and spread, but not so much that they trigger stress pathways and inhibit proliferation. 

This delicate balance can be disrupted. While traditionally, research has focused on inhibiting oncogenic signaling to slow cancer growth, REWIRE-CAN is taking the opposite approach. 

“REWIRE-CAN explores the counterintuitive principle that deliberate hyperactivation of oncogenic signaling can destabilize cancer cells by pushing signaling beyond tolerable thresholds,” Vanhaesebroeck explained.  

“This approach exploits the fact that cancer cells often already operate close to the limits of signaling balance and exist under chronic stress conditions, including nutrient deprivation and hypoxia, chromosomal instability and replication stress, and immune pressure.” 

Hyperactivation of cancer growth signaling disrupts homeostasis and triggers metabolic and cellular stress, causing cell death.  

Genetic activation studies have pinpointed multiple oncogenic pathways, including MAPK, PI3K, and WNT signaling, as potentially lethal to cancer cells when pushed beyond their optimal threshold. 

To use hyperactivation as a therapeutic strategy, researchers are investigating compounds that can either directly activate oncogenic signaling or inhibit negative regulators. 

“Emerging evidence from first-generation pharmacological oncogene activators—several of which were developed by REWIRE-CAN members and their collaborators—indicates that drug-based hyperactivation, like genetic hyperactivation, can lead to cancer cell death,” said Vanhaesebroeck. 

These oncogene activators, combined with other drugs, could also be used to reprogram treatment-resistant cancer cells. 

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Forcing treatment-resistant states to become drug-sensitive 

Drug resistance is a major challenge in cancer treatment. In some cases, molecular differences in small groups of cancer cells make them insensitive to a particular treatment. They survive the course of treatment, continue to grow, and reform tumors. In other cases, cancer cells acquire molecular changes that confer resistance to the drug as it’s being administered. 

“After cancer cells have been established by genomic alterations, they can transition into drug-resistant states through signaling and epigenetically driven processes that are reversible by pharmacological manipulation,” Vanhaesebroeck explained. “By modulating these regulatory circuits, it is possible to force drug-resistant cancer cells into alternative, drug-sensitive states.” 

The compounds used to force this change in cell state do not need to be cytotoxic; instead, “they act as cell state engineering tools that reshape signaling and transcriptional landscapes,” he said.

This reprogramming creates a window during which cancer cells are vulnerable to therapies or where previously ineffective therapies regain their potency.  

Creating “bottlenecks” in cancer cell plasticity 

The capacity of cancer cells to make dynamic, multi-directional changes in their cell states is referred to as cancer cell plasticity.  

“Cancer cell plasticity allows cancer cells to adopt many different states, enabling adaptation, relapse, and spread,” noted Vanhaesebroeck.  

Plasticity is a major contributor to cancer drug resistance, as exposure to therapies can trigger cells to transition from drug-sensitive to drug-resistant states. This shift is associated with epigenetic, transcriptional, and signaling pathway changes. 

“REWIRE-CAN aims to deliberately limit this flexibility by creating bottlenecks—forcing cells into a small number of constrained, drug-treatable states,” said Vanhaesebroeck. 

Fixing cells in a drug-sensitive state prevents them from further adaptation and subsequent resistance, allowing the cancer to be fully eliminated by therapy. 

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Unraveling and targeting the molecular mechanisms behind cancer cell plasticity and combining these agents with existing anticancer regimens could yield better outcomes for patients.  

Identifying promising pathways for rewiring in cancer  

The REWIRE-CAN team is focusing on colorectal cancer, which is the second most common cause of cancer death. An alarming rise in the incidence of colorectal cancer in young adults is further prompting research into new therapeutic approaches. 

Using a deeply annotated biobank of patient-derived colorectal cancer organoids, the REWIRE-CAN team plans to identify cellular pathways that drive treatment resistance or can be overactivated to drive the cancer cells to self-destruct. 

High-throughput functional screening will be used to pinpoint these pathways, and complementary in vivo screens in mice will capture how cancer cells rewire themselves within the tumor microenvironment.  

“Members of the REWIRE-CAN team have developed novel approaches that allow us to systematically test hundreds of drug combinations, including pathway activators, across genetically diverse patient‑derived samples,” said Vanhaesebroeck. “This approach directly addresses patient heterogeneity and highlights conserved, therapeutically actionable pathways that are most amenable to pharmacological rewiring.” 

Challenges in using cell rewiring as a therapeutic approach 

While promising, using cancer cell rewiring as a therapeutic approach is not without its challenges.

“This is a largely unexplored area with many unknowns.” — Prof. Bart Vanhaesebroeck 

Hyperactivating cancer pathways represents an entirely new therapeutic approach. Pathway-activating drugs, therefore, potentially face challenges with drug tolerability, Vanhaesebroeck outlined. 

“Another possible risk is cancer promotion by activators, which we will address through a comprehensive suite of experimental strategies,” he continued. 

“This is precisely why this proposal is well-suited to a Cancer Grand Challenge: it tackles a fundamental problem that can only be addressed through coordinated international effort.”