Can anyone elaborate how the drug resistance mechanism of cancer is consequence of multipathway connectivity.
Hi, Ashwani, good day. See if the attached three articles can provide you information you need or not.
In general a patient may develop resistance to a drug by acquiring genetic or epigenetic changes which eventually leads to some biochemical changes that include 1)elevated double-strand DNA break repair ( DDR). This pathway is mediated by ATM ( Ataxia telangiectasia mutated) gene.
2) decreased apoptotic response- mediated by anti apoptotic pathway
3) Cellular Stress Responses- NF-B Pathway
- tumor microenvironment reduces oxygen radicals generated by anti tumor drugs
All these pathways may be a useful targets for the development of new anticancer drugs.
Definitely Yes. Due to tumor heterogeneity, there are different tumor cell population addicted to different oncogene pathway. Its always beneficial for patient to give double or triple combination over single drug to target multiple signaling pathways at same time. And double and triple drug combinations have been proved more efficacious in clinical settings. The only downside of combination therapy is side effects.
Drug resistance is a complex phenomena in Cancer cells. After repetitive exposure to cancer drugs the cells initiate mutational changes such that it can protect itself from toxic drugs. It is a self protective mechanism for the cancer cells
Cancer resistance, at least for the case of kinase inhibiting drugs, may have one of many potential origins as detailed by Wagle et al. ( J. Clinical Oncol 29(22), 2011) and others. These may be roughly summarized as follows:
(1) Secondary mutation of the target kinase. Ex: BCR-ABL is resistant to Dasatinib because of a secondary mutation different from the one that resisted the effect of Gleevec (imatinib) and for which Dasatinib was shown to be effective.
(2) Downstream mutation, as is the case for Vemurafenib inhibition of BRAF shown to be accompanied with a RAS-ERK MAPK pathway compensation, driven by a MEKC121S mutation ( MEK is downstream of BRAF). On the other hand the inhibition of MEK itself, by Selumetinib, is accompanied by a different resistant mutation : MEKP1242 .
(3) Upstream activation/amplification. Cancer cells that are resistant to MEK inhibition are found to have amplified BRAFV600E mutants (Corcoran et el. Sci Signal 3(149), 1010) . An example of resistance associated with upstream activation is the exclusive N-RAS mutation or the upregulation of PDGFRβ associated with Vemurafenib inihibition of BRAFV600E in melanomas (Nazarian et al. , Nature 468(7326), 2010)
(4) Activation of an alternate pathway (bypass) – Example: implicated MET oncogene amplification in the activation of PI3K/AKT for the case of lung cancer treatment through EGFR inhibition by gefitinib and eroltinib (Turke, et al. Cancer Cell 17(1), 2010)
Because multiple pathways create redundancies allowing the tumor cells to bypass the inhibition.
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