There are many papers that state that KRAS and EGFR mutations do not occur simultaneously or occurs very rarely together. Is there a particular reason behind this or is this predicted based on patient statistics.
I am looking particularly in Lung cancer, but this rule holds good in general from most of the papers that I have read.
Any comments on that?
Since one mutation is enough to maintain constitutive signal. Those factors share the same signal pathway, therefore double activation does not hold evolutionary benefit for the cancer cells.
This is only a dogma, which was never proved experimentally, but nobody has found simultaneous KRAS and EGFR activation mutations. However, sporadic occurrence could not be excluded.
Since one mutation is enough to maintain constitutive signal. Those factors share the same signal pathway, therefore double activation does not hold evolutionary benefit for the cancer cells.
This is only a dogma, which was never proved experimentally, but nobody has found simultaneous KRAS and EGFR activation mutations. However, sporadic occurrence could not be excluded.
As was pointed out, EGFR and KRAS are in the same pathway and therefore hyperactivation of that pathway is redundant and won't be selected for (or at least not strongly). Additionally, there is evidence from overexpression studies in cancers like melanoma, which often have a BRAF or an NRAS mutation but not usually both, that overexpression of both oncogenes can initiate apoptosis/senescence by "overloading" the system with oncogenic signaling in the same pathway. I think the lack of selective pressure for redundant oncogenes and the potential for overload may account for the infrequency of co-mutation of EGFR and KRAS. That said, there is plenty of evidence in many cancers (melanoma, lung, etc.) that when a driver oncogene is targeted (BRAF, EGFR, etc.) that other rare pre-existing clones that have secondary redundant mutations arise and take over in patients and in cell-based systems (i.e. mutant NRAS/KRAS/HRAS in mutant BRAF melanoma), so I do think these redundant mutations happen at some low to moderate frequency but aren't selected for under normal conditions, maintaining their infrequency until they are given a selective advantage.
Hope this helps..!! http://rdcu.be/yhFK
Article Molecular genetics and cellular events of K-Ras-driven tumorigenesis
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