Mechanisms of action of targeted therapies ... and mechanisms of resistance

EGFR is a tyrosine kinase (TK) receptor overexpressed in lung adenocarcinomas. EGF binding to EGFR leads to K-Ras activation, promoting signaling of division, survival, and cell invasion. Adenocarcinomas addicted to EGFR signaling pathway for proliferation (10%), exhibit mutations of EGFR tyrosine kinase domain. Inhibition of these mutated receptors favors apoptosis signaling, taking account for dramatic tumoral responses. On the other side, 30% of adenocarcinomas have K-Ras mutations making the cells resistant to EGFR TK inhibitors (TKI). Secondary resistances are induced in 50% of initially sensitive tumors by an additional EGFR mutation (T790M), lowering receptor affinity for the inhibitor. The use of high affinity inhibitors ("irreversible") is tested in those patients. In 30% of cases, secondary resistance to TKI is induced by amplification of C-Met gene that encodes for another TK receptor, stimulating cell survival by substitution to EGFR. The use of C-Met inhibitors could overcome this kind of resistance. Angiogenesis is an early event in lung cell cancerization of which main cell signaling uses TK receptors to VEGF Inhibition of this pathway consists in a major therapeutic advance in solid tumors. Finally, stimulation of anti-tumoral immunological response using anti-tumoral "vaccination", or agonists of innate immunity receptors, has given encouraging therapeutic preliminary results in lung cancer but needs phase 3 validation trials.