Question

Mutation of EGFR or Ras protein often leads to cancer. For EGFR mutated cancer, antibodies have been developed to inhibit EGFR signaling. However, no effective treatment has been developed yet. Why it might be difficult to develop specific antibodies against Ras?

Answer 1

ANSWER :- About a third of all human Cancers harbour mutations in one of the K-, N- , or HRAS genes that encode an abnormal RAS protein locked in constitutively activated state that to drive malignant transformation and tumor growth. Despite more than three decades of intensive research aimed at the discovery of RAS- directed therapeutics, there are no FDA approved drugs that are broadly effective against RAS-driven cancers. Although RAS protein are often said to be "undruggable" there is mounting evidence suggesting that it may be feasible to develop direct inhibitors of RAS protein. The reason behind that is :-

• RAS will be used when two or more isoforms may be involved. RAS protein are monomeric enzymes with modest GTPase activity, but which bind GTP and GDP with high affinity.
• The active, GTP-bound form of RAS has been described as a "coiled spring", which in turn activates effector proteins. Thus, RAS protein are important regulators of multiple aspects of normal cell growth and physiology, as well as malignant transformation.
• Most importantly that the RAS mutations develop spontaneously in tumors that become resistant to radiation and/or chemotherapy, or targetted therapies, including receptor tyrosine kinase inhibitors that activates the RAS pathway.

That is why it is difficult to develop specific antibodies against RAS.