Fig. 5

Clinical therapeutic strategies to target KRAS and MYC. Scheme of the main proteins involved in the KRAS signaling pathway, as well as several reviewed inhibitors, their clinical stage and the cancer type they are used in. The different inhibitor groups are underlined: molecules that inhibit the epidermal growth factor receptor (EGFR); Src homology region 2 domain-containing phosphatase-2 protein (SHP2) inhibitors; the Son of Seventless 1 protein (SOS1) inhibitors; the mammalian target or rapamycin molecule (mTOR) inhibitors, the MAP/ERK kinase (MEK) inhibitors; inhibitors of KRAS with the G12C mutation in its inactive state (KRAS-G12C(OFF)); inhibitors of KRAS with the G12D mutation in both its inactive and active state (KRAS-G12D); inhibitors of KRAS in its active state (KRAS(ON)); and MYC inhibitors. Among the KRAS-G12C(OFF) inhibitors, Sotorasib (AMG-510) and Adagrasib (MRTX849) are already approved for non-small cell lung cancer (NSCLC) and in Phase I/II for other solid tumors. Opnurasib (JDQ443) is in Phase III clinical trial for NSCLC and in Phase Ib/II for other solid tumors, while divarasib (GDC-6036) is in Phase Ia/Ib for all solid tumors. LY3537982 is in Phase III clinical trial for NSCLC and in Phase I/II for other solid tumors. Finally, BI1823911 is in Phase I clinical trial for all solid tumors. In the case of the KRAS-G12D inhibitors, MRTX1133 is in Phase I/II clinical trial for all solid tumors, while the rest of inhibitors, ASP3082, HRS-4642 and INCB161734, are in Phase I for all solid tumors. For what refers to the KRAS(ON) inhibitors, three promising small molecules are highlighted, RMC-6291, RMC-6236 and RMC-9805. The three of them are being evaluated as monotherapy in Phase I/Ib clinical trial for all solid tumors bearing G12C mutations, multiple RAS mutations and G12D mutations, respectively. Moreover, RMC-6291 and RMC-6236 are being tested in combination with the standard of care (SoC) in a Phase Ib/II clinical trial for all solid tumors. Four direct MYC inhibitors have reached clinical stage: OTX-2002 and IDP-121 are both in Phase I/II clinical trial, the first one for hepatocellular carcinoma (HCC) and other solid tumors and the second one for hematological malignancies; OMO-103 is currently in Phase Ib for metastatic pancreatic ductal adenocarcinoma (PDAC) patients in combination with chemotherapy, and WBC100 is in Phase I for solid tumors. Finally, OTX-2101 is under investigation in preclinical studies for NSCLC. Created with BioRender.com