It is generally accepted that KRAS mutations shortcut the signal transductions which physiologically tranfer extracellular signals into nucleus. The mutated KRAS forms a blocking configuration at GTP-binding site, and becomes constitutively active. However, there are also some literatures reporting that KRAS mutated cells do not completely bypass upstream receptors. For example, in NSCLC EGFR knockdown inhibited cell proliferation in KRAS mutated cells-in a degree much more than it affected KRAS wild type cells. (BMC Med, 2012, 10: 28) There are several other papers indicating that KRAS mutated cells still need receptor tyrosine kinases to transduce signals. Does anyone have any idea about this contradiction? Is there any clinical evidence regarding this issue?
No, in pancreatic cancer EGFR is required for Kras-induced PDAC, see for example PMID: 22975375 from Barbacid and col
I don't know clinical evidence; but a good rule of thumb is mutated Ras will constitutively stimulate production of EGR ligands which will work in an autocrine manner. However a new story is emerging regarding YAP turnover which may answer your question; see Hong X et al. EMBO J 2014 (21): 2447-2457.
I think the clinical development of Cetuximab, a MAB against EGFR, might be a good clinical relevance for this question, at least in the case of colorectal cancer (CRC)... Cetuximab did not improve quality of life and/or survival as expected in CRC in early, pivotal clinical trials. Further analysis for K-ras profiling revealed that, for wild-type K-ras, Cetuximab increased median Overall Survival (OS) 4.8 to 9.5 months and Disease Free Survival (DFS) 1.9 to 3.7 months (p
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