Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils.
Bottom Line: However, in the face of such a considerable body of knowledge, the intimate molecular mechanisms mediating this phenomenon remain elusive.At the clinical level, successful translation of the oncogene addiction model into the rational and effective design of targeted therapeutics against individual oncoproteins still faces major obstacles, mainly due to the emergence of escape mechanisms and drug resistance.Here, we offer an overview of the relevant literature, encompassing both biological aspects and recent clinical insights.
Affiliation: Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo (Torino), Italy.Show MeSH
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Mentions: The genetic streamlining hypothesis stems from the well-established notion that cancer cells undergo constant genetic drift as a consequence of the selective pressure exerted by the tumourigenic process and by the tumour microenvironment. Because of this, cancer cells are thought to lose (or, better, actively dismiss) any cellular function that has proved to be non-essential for cell viability or does not provide any increase in cellular fitness (‘genome degeneration’). At the molecular level, this occurs presumably through a mutational burden of non-adaptive alterations or epigenetic modifications (‘genetic load’). When the pressure exerted by the tumour microenvironment or by tumour-autonomous features remains constant, the genetic load in non-essential genes will have little effect on cell growth dynamics (Kamb, 2003). However, the widespread silencing of subsidiary functions renders cancer cells much more susceptible to acute perturbations: sudden changes in the composition of the surrounding stroma or inhibition of one or more of the pathways still active in cancer cells lead to rapid reduction in cellular fitness and collapse (Fig 1A). Theoretically, this process may produce an opposite outcome: an initially non-adaptive mutation can coexist as a passenger alteration along with driver mutations in the genome of a cancer cell until a new selective force – for example drug exposure – unleashes its potential to increase biological fitness in that particular circumstance; this, in some instances, can foster the emergence of resistant clones (see below).
Affiliation: Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo (Torino), Italy.