Oncogene mimicry as a mechanism of main resistance to BRAF inhibitors. translation of this strategy to the medical center. Graphical Abstract INTRODUCTION The clinical effectiveness of therapeutic strategies targeting oncogenic signaling is usually often limited by mechanisms of adaptive resistance, in which initial suppression of oncogenic signaling by a drug is Sirt6 usually incomplete and temporary, followed by signaling reactivation (rebound) in the presence of the drug. Deregulated RAS/RAF/MEK/ERK signaling (extracellular signal-regulated kinase [ERK] signaling) drives growth of a large fraction of human tumors. We as well as others have shown that relief of unfavorable opinions upon RAF or MEK inhibitor treatment in multiple ERK-dependent tumor contexts, promotes upregulation of various receptor tyrosine kinases (RTKs), which, in turn, activate RAS, resulting in rebound of ERK activity and development of adaptive resistance of the tumor to the inhibitor (Corcoran et al., 2012; Duncan et al., 2012; Karoulia et al., 2016; Lito et al., 2012; Montero-Conde et al., 2013; Prahallad et al., 2012; Sun et al., Imipramine Hydrochloride 2014). The non-receptor protein tyrosine phosphatase SHP2 (effectiveness of combined ERK signaling and SHP2 inhibition, we treated mice transporting RKO xenografts with the triple combination of the U.S. Food and Drug Imipramine Hydrochloride Administration (FDA)Capproved RAF and MEK inhibitor combination (dabrafenib and trametinib, respectively) and SHP099, after confirming it was more effective than dabrafenib and trametinib in inhibiting ERK signaling (Physique Imipramine Hydrochloride 4G). Dabrafenib and trametinib or SHP099 alone had minimal effect on xenograft tumor growth or ERK signaling (Figures 4HC4J). However, the triple combination dabrafenib, trametinib, and SHP099 markedly suppressed p(Y542)SHP2 (Physique 4H) and ERK signaling (Physique 4I) and growth (Physique 4J) of RKO xenograft tumors, without any obvious effect on body weight (Physique S3C), providing further evidence that combined ERK signaling and SHP2 inhibition may be an effective therapeutic strategy for patients with BRAF(V600E) colorectal tumors. ERBB Family or MET Activation Promotes Adaptive Resistance to RAF Inhibitor via Imipramine Hydrochloride SHP2-Dependent RAS Activation in BRAF(V600E) Colorectal Tumors To dissect the molecular mechanisms underlying BRAF(V600E)-expressing thyroid and colorectal tumors with SHP2-dependent and SHP2-impartial adaptive resistance to RAF inhibition (SHP2-positive and SHP2-unfavorable, respectively), we treated cells with VEM for 48 hr, followed by different RTK inhibitors for 2 hr and examined their effect on the pERK rebound. ERBB family inhibitors (gefitinib, lapatinib, and AZD8931) potently suppressed the pERK rebound in WiDr and HT-29 cells but failed to do so in RKO cells or in any of the SHP2-unfavorable tumor Imipramine Hydrochloride cells (Physique 5A). To identify additional RTKs beyond the ERBB family that might be drivers of feedback-induced RAS activation, we performed RTK arrays after treatment with VEM in RKO and in the SHP2-unfavorable cells. In RKO, phosphorylation of multiple RTKs, including MET and AXL, was detected (Figures 5B, 5C, and S4). Treatment of RKO cells with the MET inhibitors crizotinib or cabozantinib, an inhibitor of both MET and AXL among other kinases, but not with the AXL inhibitor R428, potently suppressed the pERK rebound after VEM treatment (Figures 5C and 5D) as well as MET phosphorylation (Physique 5C). Together, these results argued that, in RKO unfavorable feedback-induced RAS, activation was mediated by MET signaling through SHP2. Open in a separate window Physique 5. Inhibitors of Users of the.