Whole-Cell Stress Sensing: A New Lens for Cancer Drug Discovery
Whole-cell stress sensing can identify cancer drugs that target previously “undruggable” proteins.
Understanding how cells sense and respond to stress is emerging as a new strategy for uncovering novel therapeutic mechanisms in oncology. As drug discovery moves beyond single-target-based approaches, researchers are increasingly looking to systems‑level biology to reveal vulnerabilities that traditional screens overlook.
Soley Therapeutics has developed a platform that captures whole‑cell stress responses in living human cells, enabling the discovery of first‑in‑class drug candidates such as STX‑6398, a CKAP2‑modulating molecule being presented at The American Association for Cancer Research (AACR) Annual Meeting 2026.
Technology Networks spoke with Dr. Yerem Yeghiazarians, co‑founder and chief executive officer at Soley Therapeutics, to discuss how whole‑cell stress sensing works, why a biology‑first approach expands the druggable landscape, and how Soley identified CKAP2 as a promising cancer target, despite it previously being deemed “undruggable”.
How whole‑cell stress sensing reveals hidden biological signals
Can you talk us through what “whole‑cell stress sensing” means and what unique biological signals this approach captures that traditional screens might miss?
Whole‑cell stress sensing begins with a simple but powerful premise: instead of anchoring discovery to a predefined target or pathway, Soley observes how human cells respond to drug-induced modulation.
Yeghiazarians explained: “We start by observing how living human cells sense and respond to drug perturbation over time, rather than beginning with a predefined target, gene, or pathway.” This reflects the complexity of disease biology, where cell fate—survival, adaptation, or death—is often determined by how stress signals interact across the system, rather than by a single broken node.
“What whole-cell stress sensing captures that traditional screens often miss is trajectory.” — Dr. Yerem Yeghiazarians
“Static assays usually give you a snapshot or a single endpoint, such as viability, pathway inhibition, or reporter activity,” said Yeghiazarians. “Those readouts can tell you what happened, but not how the cell got there.”
Soley’s platform tracks how cell behavior changes across drug dose and time, detecting cell state divergence long before conventional markers shift. This enables the team to distinguish compounds that selectively redirect cell behavior from those that cause broad damage. The trajectory-based insights from the cell sensing platform are key to identifying early stress response signatures, which can reveal mechanisms that would otherwise remain invisible.
Trajectory‑based insights from stress biology:
- Dynamic stress response profiling uncovers early divergence in cell state.
- Whole‑cell sensing distinguishes selective modulators from nonspecific cytotoxic compounds.
- Temporal data reveals mechanisms that static endpoint assays might miss.
- Systems‑level stress integration reflects how complex diseases determine cell fate.
How a biology‑first strategy expands the druggable space
How does employing a “biology-first” approach influence the types of drug targets you can pursue?
“A biology‑first approach changes the starting point of discovery,” said Yeghiazarians. “Instead of choosing a target up front and then asking how to drug it, we begin with observed human cellular responses and let the biology reveal which mechanisms actually matter for cell fate in disease.”
This opens the door to targets that are less likely to emerge from target‑first or genetic-first logic, including those with poorly understood or network-dependent mechanisms and those that appear undruggable.
“It also means we are not limited to a one-target, one-disease framework,” Yeghiazarians noted. “In oncology, we can identify compounds that selectively increase stress in cancer cells that are already near a tipping point.”
In other therapeutic areas, the same framework can identify molecules that rebalance stress and restore healthier function.
“The approach broadens the kinds of biology we can act on,” he said. “It helps us uncover first‑in‑class opportunities in settings where there may be no known or classically druggable target.
“We have promising work underway in neurodegeneration, metabolic disease, and hair regeneration, reflecting the broader applicability of this biology-first framework across complex diseases,” he continued.
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Therapeutic possibilities enabled by biology‑first discovery:
- Enables the pursuit of mechanisms that are network‑dependent or poorly understood.
- Identifies targets that would not arise from classical target‑first or genetics‑first workflows.
- Supports both stress‑increasing (oncology) and stress‑reducing (non‑oncology) therapeutic strategies.
- Creates opportunities for first‑in‑class drug discovery beyond conventional tractability.
Uncovering CKAP2: A druggable target hidden in stress‑response data
What insights from the cell stress-sensing platform enabled you to identify CKAP2 as a druggable target in cancer?
“Our platform led us to a compound-first biological signal before we had a conventional target,” explained Yeghiazarians. By analyzing how tumor cells responded to drug compounds over time, Soley's team identified a unique anti‑tumor trajectory and then worked backward through target deconvolution to uncover the underlying mechanism.
This reverse engineering process ultimately pointed to CKAP2—an intrinsically disordered protein historically viewed as difficult to drug directly.
“What strengthened the case was the consistency across multiple datasets,” said Yeghiazarians.
At AACR 2026, he will present data from a 300-tumor cell line panel, where CKAP2 expression was elevated in tumors relative to normal tissues. The sensitivity of Soley Therapeutics’ first-in-class drug candidate that modulates CKAP2, STX‑6398, correlated with CKAP2 abundance, and the phenotypic effects of STX‑6398 mirrored CKAP2 knockdown. These included changes in viability, migration, FAK signaling, and cell cycle progression.
“Those findings suggested that CKAP2 biology was not just associated with response, but central to it,” Yeghiazarians explained.
Evidence that CKAP2 is a stress‑linked cancer vulnerability:
- Compound response phenotyping revealed that CKAP2 underlies a distinctive anti‑tumor trajectory.
- CKAP2 abundance strongly correlated with STX‑6398 sensitivity across tumor models.
- The action of STX‑6398 mirrored CKAP2 knockdown across multiple functional readouts.
Mechanistic selectivity: How STX‑6398 targets tumor stress without harming healthy cells
How does STX‑6398 enable selective anti-tumor activity without harming healthy cells?
STX‑6398 leverages a fundamental difference between cancer cells and healthy cells: their relationship to stress.
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“Cancer cells often survive under chronic stress by relying on altered stress-response programs that healthy cells do not depend on to the same degree,” Yeghiazarians explained. “STX-6398 exploits a stress vulnerability that is more relevant in certain tumor cells than in healthy cells.”
By modulating CKAP2, STX‑6398 pushes these cells past a critical threshold, triggering death in cells already burdened by chronic stress while sparing healthier cells that are not living with the same degree of stress burden.
The dataset that Soley is presenting at AACR 2026 reinforces this selectivity logic. The compound disrupted CKAP2‑linked signaling and demonstrated significant in vivo anti‑tumor activity with tolerability in preclinical studies. “The findings suggest the compound is not acting like a nonspecific toxin, but through a biologically linked and potentially selective mechanism,” said Yeghiazarians.
Stress‑selective mechanisms underpinning STX‑6398:
- Exploits stress‑response dependencies unique to tumor cells.
- Demonstrates graded, CKAP2‑correlated activity across cancer models.
- Shows in vivo anti‑tumor activity with preclinical tolerability.
Advancing STX‑6398: Expanding translational evidence
What are the next steps for progressing STX‑6398 towards the clinic?
While Soley’s immediate focus is on two oncology programs further along in development, STX‑6398 remains a compelling first‑in‑class candidate within the company’s pipeline. The next phase centers on expanding the translational evidence base: refining biomarkers, deepening mechanistic understanding, prioritizing disease settings, and conducting the preclinical studies required to define the optimal development path.
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Yeghiazarians emphasized that STX‑6398 is also a proof point for the platform itself. “STX‑6398 demonstrates that our platform can identify first‑in‑class molecules for novel disease mechanisms considered difficult to pursue through conventional approaches,” he said.
Translational priorities for STX‑6398:
- Additional mechanistic studies to refine CKAP2‑linked biology.
- Biomarker development to guide patient selection.
- Disease‑setting prioritization based on stress‑response signatures.
- Preclinical studies to define the most appropriate clinical path.
Whole‑cell stress sensing is providing a new lens through which first‑in‑class drug candidates can be discovered, offering a dynamic view of cellular behavior that reveals mechanisms missed by traditional screens. Through a biology‑first approach, Soley Therapeutics is expanding the druggable landscape, identifying targets such as CKAP2 that emerge only when cell state trajectories are examined over time. STX‑6398, a CKAP2‑modulating oncology candidate, illustrates how stress‑selective mechanisms can deliver potent anti‑tumor activity while sparing healthy cells.
Key takeaways:
- Whole‑cell stress sensing captures dynamic cell‑state trajectories that static assays miss.
- A biology‑first approach reveals mechanisms and targets inaccessible to target‑first discovery.
- CKAP2 emerged as a druggable vulnerability through compound‑first phenotyping.
- STX‑6398 selectively kills tumor cells by exploiting stress‑response dependencies.
This content includes text that has been created with the assistance of generative AI and has undergone editorial review before publishing. Technology Networks' AI policy can be found here.
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