‘Undruggable’ mutation meets its match: Six-year effort yields first drug to target important cancer gene
See also: Drug discovery: Pocket of opportunity[subscription required]
Excerpt: “.,.the non-mutated protein is the beating heart of cell signalling, but mutated versions are the villainous masterminds of malignancies.”
and see K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions [subscription required]
Excerpt: “…initial evaluation of our compounds in lung cancer cell lines suggests allele-specific impairment of K-Ras function.”
1) They ignored any aspect of random mutations, natural selection, or mutation-driven evolution — probably because no experimental evidence supports that theory.
2) They focused on structures and functions altered by RNA-mediated amino acid substitutions, which are typically associated with nutrient-dependent adaptations; controlled proliferation of different cell types; and the pheromone-controlled physiology of reproduction.
3) That allowed them to use what is known about the difference between effects of mutations on structure and function — probably by comparing those detrimental effects in the context of the conserved molecular mechanisms of adaptations that benefit individual survival and species survival in species from microbes to man.
I say probably, but think they are obviously following the guidelines set forth by the FDA , NIMH, ASAM, and IOM for drug development. Clearly, they did not take a “shot-in-the-dark and deal-with-the-side-effects-later” approach. That’s why their approach is more likely to result in development of a potentially effective drug to treat cancer, which will hopefully not interfere, or will interfere less, with the structure and function of species-specific adaptations.
The NIMH has advocated the same approach for drug development in cases where effects on molecular mechanisms are tractable to effects on hormones that affect behavior.
Evolutionary theorists and human ethologists may now begin to see the relevance of my question about Mutation-initiated natural selection for melanoma. “This brings up the question of how the mutation was naturally selected to remain in the human genome despite the consequence of cancer.”
Anyone who cannot see that mutation-initiated natural selection in not a scientific approach will probably be among a minority of people who still do not recognize the importance of epigenetics and conserved molecular mechanisms in the context of health, mental disorders, and the treatment of physical diseases such as cancer.
Clearly, an allele-specific approach to atypical intercellular signaling associated with abnormal cell-type differentiation and proliferation is required, not just a “kill-the-mutated-cells” and accept the collateral damage approach.
Perhaps funding for social science research that is based on mutation-initiated changes that “just happen” should be held until a cure for cancer is a reality, since mutation-driven evolution has nothing to do with scientific reality.