Unraveling Key Signaling Pathways to Overcome Drug Resistance and Cancer Progression

The emergence of drug resistance remains one of the greatest challenges in effective cancer therapy. Despite advances in targeted treatments and immunotherapies, many patients relapse due to the activation of compensatory molecular mechanisms that allow tumor cells to survive and proliferate. Understanding the signaling pathways that drive this resistance is critical for developing next-generation therapeutic strategies. Among the most prominent are the PI3K/AKT/mTOR and MAPK/ERK cascades, which regulate cell survival, growth, and metabolism. Dysregulation of these pathways has been strongly associated with both intrinsic and acquired resistance to chemotherapy and targeted agents.

Aberrant activation of the PI3K/AKT/mTOR pathway enables cancer cells to bypass apoptosis and maintain survival under therapeutic pressure. Similarly, persistent stimulation of the MAPK/ERK pathway promotes uncontrolled proliferation and adaptation to kinase inhibitors. Crosstalk between these pathways further amplifies resistance, creating a robust network that is difficult to dismantle with single-agent therapies.

To overcome this challenge, researchers are turning to rationally designed combination therapies. Dual inhibition of PI3K/AKT/mTOR and MAPK/ERK pathways has shown promise in preclinical models, while targeting auxiliary pathways such as JAK/STAT, NF-κB, and Wnt/β-catenin may further enhance efficacy. Advances in single-cell sequencing and multi-omics profiling now enable precise identification of pathway alterations, opening the door to personalized treatment strategies.

This Research Topic will focus on, but is not limited to

• Investigating PI3K/AKT/mTOR and MAPK/ERK crosstalk to design effective dual inhibitors.

• Exploring the role of tumor microenvironment and stromal interactions in drug resistance.

• Targeting cancer stem cells to prevent recurrence and metastatic spread.

• Utilizing single-cell multi-omics to identify patient-specific resistance signatures.

• Developing immunotherapy combinations that overcome signaling-driven immune evasion.

• Designing adaptive clinical trials to rapidly test pathway-targeted combinations.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Technology and Code

Keywords: Drug Resistance; Cancer Progression; Signaling Pathways; Targeted Therapies; Precision Medicine

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.