Targeting Receptor Tyrosine Kinase Signaling Pathway For Personalized Cancer Diagnosis And Treatment

Cancer is a disease of abnormal cell growth.Receptor tyrosine kinases(RTKs)are key signaling molecules in regulating cancer cell growth.Multiple RTK inhibitors(RTKis)have been approved for treatments of the cancer patients with aberrant activation of RTKs(overexpression,point mutations,and translocations).The RTKi treatments are more selective and safer compared with the conventional cytotoxic cancer drugs.However,most of patients develop acquired drug resistance after treatments.Moreover,there is no guidance for the patients without RTK mutations to use the RTKi treatments.Therefore,new diagnosis and treatment strategies for effectively using RTKis are urgently needed.In our project,we have systematically studied RTK activation patterns in a panel of cancer cell lines,xenografts and primary samples from ten different tissues origins.About 80% of them express more than one activated RTKs.Combinations of specific RTKis preferentially inhibited the proliferation of the cancer cells with corresponding RTK activation patterns by inducing G1 cell cycle arrest.The RTKi combinations could simultaneously inhibit the AKT and ERK pathways and decrease the protein level of transcription factor c-MYC.We also found that the RTK activations were regulated by both cell-autonomous and environment-dependent mechanisms.Therefore,RTKi combinations based on the RTK phosphorylation patterns in the specific circumstances could efficiently inhibit the cancer cell growth.Many cancer cells,particularly the CRC cells,contain KRAS or BRAF mutations that constitutively activate AKT and/or ERK signaling pathways,independent of RTK activations.Therefore,we collected KRAS/BRAF mutant CRC cell lines and studied the therapeutic strategies based on RTK activations and their downstream signaling protein mutations.The RTKi combination,AKT inhibitor(AKTi),or MEK inhibitor(MEKi)alone could not efficiently inhibit downstream AKT and ERK pathways and cancer cell growth.AKT can be reactivated after AKTi treatment through the RTK-IRS1-PI3K-PDK1-AKT pathway.The RTK-independent CRAF activation regulates the ERK activation after MEKi treatment.Concomitant inhibition of RTKs and downstream AKT could synergistically inhibit the growth of KRAS/BRAF mutant CRC cells by complete inhibition of AKT activation.We therefore propose a RTK signaling pathway-based strategy for cancer diagnosis and treatment.Tumor tissues are tested for the genomic mutations of RTKs,KRAS and BRAF,as well as the phosphorylation of RTKs.Specific RTKis or the combinations of RTKis and AKTi are used for the treatments.