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Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils.

Torti D, Trusolino L - EMBO Mol Med (2011)

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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo (Torino), Italy.

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Models of oncogene addictionThe ‘genetic streamlining’ theory postulates that non-essential pathways (top, light grey) are inactivated during tumour evolution, so that dominant, addictive pathways (red) are not surrogated by compensatory signals. Upon abrogation of dominant signals, there is a collapse in cellular fitness and cells experience cell-cycle arrest or apoptosis (bottom, red to yellow shading).In the ‘oncogenic shock’ model, addictive oncoproteins (e.g. RTKs, red triangle) trigger at the same time pro-survival and pro-apoptotic signals (top, red and blue pathway, respectively). Under normal conditions, the pro-survival outputs dominate over the pro-apoptotic ones (top), but following blockade of the addictive receptor, the rapid decline in the activity of survival pathways (dashed lines, bottom) subverts this balance in favour of death-inducing signals, which tend to last longer and eventually lead to apoptotic death.Two genes are considered to be in a synthetic lethal relationship when loss of one or the other is still compatible with survival but loss of both is fatal. In the top panel, biochemical inactivation of pathway A (grey) has no effect on cell viability because pathway B (red), which converges at some point on a common substrate or effector (yellow), has compensating activity. When the integrity of pathway B is disrupted (bottom), the common downstream biochemical function is lost and again cancer cells may experience cell cycle arrest or apoptosis.
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fig01: Models of oncogene addictionThe ‘genetic streamlining’ theory postulates that non-essential pathways (top, light grey) are inactivated during tumour evolution, so that dominant, addictive pathways (red) are not surrogated by compensatory signals. Upon abrogation of dominant signals, there is a collapse in cellular fitness and cells experience cell-cycle arrest or apoptosis (bottom, red to yellow shading).In the ‘oncogenic shock’ model, addictive oncoproteins (e.g. RTKs, red triangle) trigger at the same time pro-survival and pro-apoptotic signals (top, red and blue pathway, respectively). Under normal conditions, the pro-survival outputs dominate over the pro-apoptotic ones (top), but following blockade of the addictive receptor, the rapid decline in the activity of survival pathways (dashed lines, bottom) subverts this balance in favour of death-inducing signals, which tend to last longer and eventually lead to apoptotic death.Two genes are considered to be in a synthetic lethal relationship when loss of one or the other is still compatible with survival but loss of both is fatal. In the top panel, biochemical inactivation of pathway A (grey) has no effect on cell viability because pathway B (red), which converges at some point on a common substrate or effector (yellow), has compensating activity. When the integrity of pathway B is disrupted (bottom), the common downstream biochemical function is lost and again cancer cells may experience cell cycle arrest or apoptosis.

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).


Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils.

Torti D, Trusolino L - EMBO Mol Med (2011)

Models of oncogene addictionThe ‘genetic streamlining’ theory postulates that non-essential pathways (top, light grey) are inactivated during tumour evolution, so that dominant, addictive pathways (red) are not surrogated by compensatory signals. Upon abrogation of dominant signals, there is a collapse in cellular fitness and cells experience cell-cycle arrest or apoptosis (bottom, red to yellow shading).In the ‘oncogenic shock’ model, addictive oncoproteins (e.g. RTKs, red triangle) trigger at the same time pro-survival and pro-apoptotic signals (top, red and blue pathway, respectively). Under normal conditions, the pro-survival outputs dominate over the pro-apoptotic ones (top), but following blockade of the addictive receptor, the rapid decline in the activity of survival pathways (dashed lines, bottom) subverts this balance in favour of death-inducing signals, which tend to last longer and eventually lead to apoptotic death.Two genes are considered to be in a synthetic lethal relationship when loss of one or the other is still compatible with survival but loss of both is fatal. In the top panel, biochemical inactivation of pathway A (grey) has no effect on cell viability because pathway B (red), which converges at some point on a common substrate or effector (yellow), has compensating activity. When the integrity of pathway B is disrupted (bottom), the common downstream biochemical function is lost and again cancer cells may experience cell cycle arrest or apoptosis.
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Related In: Results  -  Collection

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fig01: Models of oncogene addictionThe ‘genetic streamlining’ theory postulates that non-essential pathways (top, light grey) are inactivated during tumour evolution, so that dominant, addictive pathways (red) are not surrogated by compensatory signals. Upon abrogation of dominant signals, there is a collapse in cellular fitness and cells experience cell-cycle arrest or apoptosis (bottom, red to yellow shading).In the ‘oncogenic shock’ model, addictive oncoproteins (e.g. RTKs, red triangle) trigger at the same time pro-survival and pro-apoptotic signals (top, red and blue pathway, respectively). Under normal conditions, the pro-survival outputs dominate over the pro-apoptotic ones (top), but following blockade of the addictive receptor, the rapid decline in the activity of survival pathways (dashed lines, bottom) subverts this balance in favour of death-inducing signals, which tend to last longer and eventually lead to apoptotic death.Two genes are considered to be in a synthetic lethal relationship when loss of one or the other is still compatible with survival but loss of both is fatal. In the top panel, biochemical inactivation of pathway A (grey) has no effect on cell viability because pathway B (red), which converges at some point on a common substrate or effector (yellow), has compensating activity. When the integrity of pathway B is disrupted (bottom), the common downstream biochemical function is lost and again cancer cells may experience cell cycle arrest or apoptosis.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo (Torino), Italy.

Show MeSH
Related in: MedlinePlus