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Druggable drivers of lung cancer.

Fawdar S, Edwards ZC, Brognard J - Oncotarget (2013)

View Article: PubMed Central - PubMed

Affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute and The University of Manchester, Manchester, UK.

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However, the number of patients that can be treated with targeted therapies is limited by our understanding of the genetic drivers that are required to maintain cancer cell survival and proliferation... To tackle this enormous challenge presented to the research community we applied a targeted genetic dependency approach to discover functionally relevant somatically mutated proteins required to maintain lung cancer cell survival and growth... As n-of-1 clinical trials become a real possibility one could envisage isolating tumor cells from a biopsy, performing next-generation sequencing, establishing a cell line and screening all somatic mutants to identify individual Achilles' heels that can be targeted therapeutically... The mutation frequency for the genes we identified ranged from 2-10% of lung cancers; given the frequency of lung cancer in the population, these targets could be exploited by pharmaceutical companies for drug development... Indeed PAK5 mutations have been identified in 9% of lung adenocarcinomas and if approximately half of these were gain-of-function mutations (we observed 4 out of 7 PAK5 mutants had increased activity compared to wild-type PAK5), this would represent a sizable patient population (approximately 65,000 patients/year globally) that could benefit from targeted inhibition of the PAK5 kinase... An important finding from our study was the identification of mutations that act in concert to hyper-activate a specific pathway... For example, in one cancer cell line we observed an accumulation of activating mutations that converge towards the same central pathway to confer a proliferative advantage to the cell; specifically, we observed that the intermediately activating mutation BRAF can cooperate with PAK5 and NRAS to drive and maintain tumor growth via the RAF/MEK/ERK signaling axis... Thus a patient presenting to the clinic with a similar mutational profile would preferentially benefit from a pan-RAF or MEK inhibitor rather than a single BRAF-specific inhibitor... Furthermore, by identifying the individual hyper-activated components of the pathway, a combination therapy of targeted pharmacological inhibitors may prove to be more successful and better tolerated by the patient... In summary, targeted genetic dependency screens represent a valuable strategy to identify low frequency oncogenic mutations and can complement more traditional bioinformatic approaches; these tend to be selective for loss-of-function mutations as alterations in key residues required to maintain enzymatic activity are those most likely to be predicted as damaging.

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Targeted genetic dependency screen to identify novel actionable mutations; mutated FGFR4, MAP3K9 and PAK5 are illustrated examplesPatient tumors are exome sequenced and treatment is stratified based upon the mutational profile of each individual. Treatment options include novel pharmacological compounds to specifically inhibit driver oncogenes, and/or targeting the main downstream hyper-activated pro-proliferative signaling pathway, for example inhibition of MEK.
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Figure 1: Targeted genetic dependency screen to identify novel actionable mutations; mutated FGFR4, MAP3K9 and PAK5 are illustrated examplesPatient tumors are exome sequenced and treatment is stratified based upon the mutational profile of each individual. Treatment options include novel pharmacological compounds to specifically inhibit driver oncogenes, and/or targeting the main downstream hyper-activated pro-proliferative signaling pathway, for example inhibition of MEK.


Druggable drivers of lung cancer.

Fawdar S, Edwards ZC, Brognard J - Oncotarget (2013)

Targeted genetic dependency screen to identify novel actionable mutations; mutated FGFR4, MAP3K9 and PAK5 are illustrated examplesPatient tumors are exome sequenced and treatment is stratified based upon the mutational profile of each individual. Treatment options include novel pharmacological compounds to specifically inhibit driver oncogenes, and/or targeting the main downstream hyper-activated pro-proliferative signaling pathway, for example inhibition of MEK.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824536&req=5

Figure 1: Targeted genetic dependency screen to identify novel actionable mutations; mutated FGFR4, MAP3K9 and PAK5 are illustrated examplesPatient tumors are exome sequenced and treatment is stratified based upon the mutational profile of each individual. Treatment options include novel pharmacological compounds to specifically inhibit driver oncogenes, and/or targeting the main downstream hyper-activated pro-proliferative signaling pathway, for example inhibition of MEK.

View Article: PubMed Central - PubMed

Affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute and The University of Manchester, Manchester, UK.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

However, the number of patients that can be treated with targeted therapies is limited by our understanding of the genetic drivers that are required to maintain cancer cell survival and proliferation... To tackle this enormous challenge presented to the research community we applied a targeted genetic dependency approach to discover functionally relevant somatically mutated proteins required to maintain lung cancer cell survival and growth... As n-of-1 clinical trials become a real possibility one could envisage isolating tumor cells from a biopsy, performing next-generation sequencing, establishing a cell line and screening all somatic mutants to identify individual Achilles' heels that can be targeted therapeutically... The mutation frequency for the genes we identified ranged from 2-10% of lung cancers; given the frequency of lung cancer in the population, these targets could be exploited by pharmaceutical companies for drug development... Indeed PAK5 mutations have been identified in 9% of lung adenocarcinomas and if approximately half of these were gain-of-function mutations (we observed 4 out of 7 PAK5 mutants had increased activity compared to wild-type PAK5), this would represent a sizable patient population (approximately 65,000 patients/year globally) that could benefit from targeted inhibition of the PAK5 kinase... An important finding from our study was the identification of mutations that act in concert to hyper-activate a specific pathway... For example, in one cancer cell line we observed an accumulation of activating mutations that converge towards the same central pathway to confer a proliferative advantage to the cell; specifically, we observed that the intermediately activating mutation BRAF can cooperate with PAK5 and NRAS to drive and maintain tumor growth via the RAF/MEK/ERK signaling axis... Thus a patient presenting to the clinic with a similar mutational profile would preferentially benefit from a pan-RAF or MEK inhibitor rather than a single BRAF-specific inhibitor... Furthermore, by identifying the individual hyper-activated components of the pathway, a combination therapy of targeted pharmacological inhibitors may prove to be more successful and better tolerated by the patient... In summary, targeted genetic dependency screens represent a valuable strategy to identify low frequency oncogenic mutations and can complement more traditional bioinformatic approaches; these tend to be selective for loss-of-function mutations as alterations in key residues required to maintain enzymatic activity are those most likely to be predicted as damaging.

Show MeSH
Related in: MedlinePlus