The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Dias, M. H. et al. Cancer Discovery. 14 (7): 1276–1301 (2024).
doi: 10.1158/2159-8290.CD-23-0216.
Summary of the findings
Summary of the findingsThis study presents a novel and counterintuitive cancer therapy approach that paradoxically activates oncogenic pathways, exploiting cancer cells’ reliance on stress response mechanisms for survival. Using colorectal cancer models, the researchers demonstrated that inhibiting Protein Phosphatase 2A (PP2A) with the drug LB-100 overactivates multiple oncogenic pathways in cancer cells. While these pathways typically drive cancer growth, their overactivation causes significant cellular stress, pushing the cells toward a breaking point. The addition of a WEE1 inhibitor further disrupted the cells’ ability to manage this stress by impairing DNA damage repair and cell cycle checkpoints, leading to catastrophic mitotic failure and eventual cell death.
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Notably, the combination of LB-100 and the WEE1 inhibitor was highly effective across various cancer models, including patient-derived tumors, highlighting its broad applicability. Additionally, cancer cells that developed resistance to the treatment lost their ability to form tumors, suggesting a significant reduction in their malignancy. These results underscore the potential of targeting cancer cells’ inherent vulnerabilities through stress-induced lethality. By combining two agents to target the very nature of cancer cells, this strategy offers a promising alternative for combating drug-resistant cancers with potential applications beyond colorectal cancer. It also addresses a critical need for therapies that prevent recurrence and tumor progression.
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Future impact
This research introduces a fundamentally different approach to cancer treatment by exploiting core vulnerabilities of cancer cells through paradoxical activation of oncogenic pathways. The combination described in the manuscript and others based on the same rationale may be a powerful strategy to target drug-resistant and aggressive cancers, with potential applications across various tumor types. The findings could inspire the development of novel combination therapies that use cancer cells’ “powers” against them. This approach may significantly improve outcomes for patients with advanced cancers, paving the way for more effective and durable therapeutic options in oncology.
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