It is clear by now that CRISPR screens are a useful tool to identify and validate novel targets for the treatment of various malignancies. Furthermore, genetic screens have allowed the identification of not only the usual kinases but also other genes with different functions in the cell such as epigenetic regulators or phosphatases. SHP2 was discovered in a dropout genetic screen with a phosphatase library as driver of resistance to targeted therapies. As a consequence, SHP2 became an attractive target for BRAF-mutant colorectal tumors that are unresponsive to vemurafenib. Recently, pharmaceutical companies developed specific inhibitors for SHP2. This allowed a more translational investigation of this drug in combination with other approved or experimental targeted therapies. In fact, this thesis titled “All roads lead to SHP2” explores the inhibition and depletion of SHP2 in several tumor types. Specifically, we show that SHP2 suppression in combination with MEK inhibitors, both in vitro and in vivo, improves the tumor control in the context of KRAS-mutant NSCLC tumors. Importantly, we demonstrate here that even though mutant KRAS is overactive, it remains dependent on upstream signaling from growth factor receptors, and thereby SHP2. We validate a different SHP2 inhibitor, RMC-4550, in combination with an ERK inhibitor for the treatment of KRAS-mutant pancreatic adenocarcinomas. This extensive pre-clinical validation with these two specific inhibitors led to the SHERPA phase 1/1b clinical trial, currently testing this combination in patients harboring KRAS-mutant tumors. We seek for mechanisms of resistance to dual blockade of SHP2 and ERK in the context of KRAS-mutant PDAC. Interestingly, we observe two main ways to become resistant to our combination. First, we observed that PTEN deletion can activate the PI3K-AKT-mTOR pathway, and thereby drive survival and proliferation of the tumor cells. Second, depletion of either DET1 or COP1 can lead to resistance to our combination by activating the JUN pathway. Moreover, spontaneously generated resistant cells have increased activity of both mTOR and JUN signaling pathways. We investigate why HCC tumors are unresponsive to mTOR inhibition since 40-50% of these tumors depend on the mTOR pathway. We observe that upregulation of different receptor tyrosine kinases is triggered upon mTOR inhibition. It is important to note that SHP2 is downstream of nearly all receptor tyrosine kinases and upstream of RAS, hence affecting the transduction of signaling from the RTKs to the MAPK pathway as well as the PI3K-AKT-mTOR pathway, two main pathways for cancer cells to proliferate, grow and survive. Following the title of this thesis, we observe SHP2 is commonly activated upon mTOR inhibition. We also combine 3 different SHP2 inhibitors with AZD8055, an mTOR dual kinase inhibitor, in the context of hepatocellular carcinoma. In vivo, we observe greater responses with the combination compared to the monotherapies. Importantly, we show that the combination is effective in a tumor intrinsic manner by downregulating MYC and KRAS signaling. Finally, we summarize and discuss all the findings presented in this thesis. We hypothesize and speculate about the future of SHP2 drugs in cancer therapy.