Acquired resistance to molecularly targeted therapies for cancer

Abstract

Acquired resistance to molecularly targeted therapies remains a formidable challenge in the treatment of cancer, despite significant advancements over the last several decades. We critically evaluate the evolving landscape of resistance mechanisms to targeted cancer therapies, with a focus on the genetic, molecular, and environmental contributors across a variety of malignancies. Intrinsic mechanisms such as mutations, drug and drug target modifications, and, notably, the activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways are mechanisms different malignancies use to combat therapeutic effectiveness. Furthermore, extrinsic alterations to the tumor microenvironment contribute to therapeutic resistance. We highlight similarities and differences in mechanisms across a wide spectrum of cancers including hematologic malignancies, non-small cell lung cancer, gastrointestinal, breast, and prostate cancers, pancreatic, ovarian, endometrial, and intracranial gliomas. Emerging strategies to overcome resistance, including multi-targeted approaches, combination therapies, and exploitation of synthetic lethality, are all critically discussed. We advocate for a nuanced understanding of resistance mechanisms as a cornerstone for developing future therapeutic strategies, emphasizing the necessity for integrated approaches that encompass genomic insights and precision medicine to outpace the dynamic and complex nature of cancer evolution and therapy resistance.

Keywords: Molecular targeted therapies; acquired resistance; cancer treatment strategies; precision medicine.

Figure 1

Schematic representation of parallels between PI3K/Akt and MAPK signal pathways. Both pathways become activated when growth factors bind to their respective RTKs, causing RAS GTPases to relay signals downstream. Activation of these pathways promotes increased cell proliferation and survival. Some of the intricacies in signaling by mTORC1 and mTORC2 are shown leading to some distinct effects on metabolism and cell fate. PI3K: Phosphoinositide 3-kinase; Akt: protein kinase B; MAPK: mitogen activated protein kinase; RTK: receptor tyrosine kinase; RAS: oncogene; PTEN: phosphatase and tensin homolog; PIP₂: phosphatidylinositol 4,5-bisphosphate; PIP₃: phosphatidylinositol 3,4,5-triphosphate; PDK1: 3-phosphoinositidedependent protein kinase 1; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; RAF: rapidly accelerated fibrosarcoma; MEK: mitogen-activated extracellular signal-regulated kinase; ERK: extracellular signal-related kinase. Created in BioRender. Purcell, C. (2025) https://BioRender.com/3us5vg.

Figure 2

Exploitation of synthetic lethality in cancer therapy. The concept of synthetic lethality is represented along with examples of its clinical or experimental use in cancer therapy. Created in BioRender. Purcell, C. (2025) https://BioRender.com/hbbdh35.