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Colorectal cancer (CRC) is a highly prevalent and lethal cancer worldwide. Approximately 45% of CRC patients harbor a gain-in-function mutation in KRAS. KRAS is the most frequently mutated oncogene accounting for approximately 25% of all human cancers. Gene mutations in KRAS cause constitutive activation of the KRAS protein and MAPK/AKT signaling, resulting in unregulated proliferation and survival of cancer cells and other aspects of malignant transformation, progression, and metastasis. While KRAS has long been considered undruggable, the FDA recently approved two direct acting KRAS inhibitors, Sotorasib and Adagrasib, that covalently bind and inactivate KRASG12C. Both drugs showed efficacy for patients with non-small cell lung cancer (NSCLC) diagnosed with a KRASG12C mutation, but for reasons not well understood, were considerably less efficacious for CRC patients diagnosed with the same mutation. Thus, it is imperative to understand the basis for resistance to KRASG12C inhibitors, which will likely be the same limitations for other mutant specific KRAS inhibitors in development. This review provides an update on clinical trials involving CRC patients treated with KRASG12C inhibitors as a monotherapy or combined with other drugs. Mechanisms that contribute to resistance to KRASG12C inhibitors and the development of novel RAS inhibitors with potential to escape such mechanisms of resistance are also discussed. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a highly prevalent and lethal cancer worldwide. Approximately 45% of CRC patients harbor a gain-in-function mutation in KRAS. KRAS is the most frequently mutated oncogene accounting for approximately 25% of all human cancers. Gene mutations in KRAS cause constitutive activation of the KRAS protein and MAPK/AKT signaling, resulting in unregulated proliferation and survival of cancer cells and other aspects of malignant transformation, progression, and metastasis. While KRAS has long been considered undruggable, the FDA recently approved two direct acting KRAS inhibitors, Sotorasib and Adagrasib, that covalently bind and inactivate KRASG12C. Both drugs showed efficacy for patients with non-small cell lung cancer (NSCLC) diagnosed with a KRASG12C mutation, but for reasons not well understood, were considerably less efficacious for CRC patients diagnosed with the same mutation. Thus, it is imperative to understand the basis for resistance to KRASG12C inhibitors, which will likely be the same limitations for other mutant specific KRAS inhibitors in development. This review provides an update on clinical trials involving CRC patients treated with KRASG12C inhibitors as a monotherapy or combined with other drugs. Mechanisms that contribute to resistance to KRASG12C inhibitors and the development of novel RAS inhibitors with potential to escape such mechanisms of resistance are also discussed.

Castration-resistant prostate cancer (CRPC) is a progressed stage of prostate cancer, which requires better understanding of the mechanisms and remains an unmet clinical need. As a common oncogene, K-Ras is associated with malignant behavior in different types of tumors but its role in CRPC is unknown. The present study aims to find the mechanism of K-Ras in CRPC and whether it can be used as a crucial molecule for the treatment of CRPC. For this purpose, tissue samples from primary prostate cancer (PPC) and CRPC patients were analyzed by immunohistochemistry and the data showed that K-Ras was elevated in CRPC. More importantly, higher K-Ras expression was related to a shorter recurrence-free survival time in patients with CRPC. In addition, K-Ras promoted the invasion, migration, and drug resistance of CRPC cells by activation of PLCε/PKCε signaling pathway. Meanwhile, the inhibitor of K-RasG12C mutants was able to inhibit malignant behavior of CRPC cells in vitro and in vivo. Inhibitors of K-RasG12C mutants have entered clinical trials. Taken together, the study shows that K-Ras may activate PKCε through PLCε, resulting in the alterations of malignant behavior of CRPC. Inhibitor 9, an inhibitor of the K-RasG12C mutant, has a strong anti-tumor effect in CRPC, which potentially suggests that inhibitors of this nature may serve as a promising treatment for CRPC.

Castration-resistant prostate cancer (CRPC) is a progressed stage of prostate cancer, which requires better understanding of the mechanisms and remains an unmet clinical need. As a common oncogene, K-Ras is associated with malignant behavior in different types of tumors but its role in CRPC is unknown. The present study aims to find the mechanism of K-Ras in CRPC and whether it can be used as a crucial molecule for the treatment of CRPC. For this purpose, tissue samples from primary prostate cancer (PPC) and CRPC patients were analyzed by immunohistochemistry and the data showed that K-Ras was elevated in CRPC. More importantly, higher K-Ras expression was related to a shorter recurrence-free survival time in patients with CRPC. In addition, K-Ras promoted the invasion, migration, and drug resistance of CRPC cells by activation of PLCε/PKCε signaling pathway. Meanwhile, the inhibitor of K-RasG12C mutants was able to inhibit malignant behavior of CRPC cells in vitro and in vivo. Inhibitors of K-RasG12C mutants have entered clinical trials. Taken together, the study shows that K-Ras may activate PKCε through PLCε, resulting in the alterations of malignant behavior of CRPC. Inhibitor 9, an inhibitor of the K-RasG12C mutant, has a strong anti-tumor effect in CRPC, which potentially suggests that inhibitors of this nature may serve as a promising treatment for CRPC. [ABSTRACT FROM AUTHOR]

Retraction: Inhibitor 9 Combined With Androgen Deprivation Therapy or Chemotherapy Delays the Malignant Behavior of Castration-Resistant Prostate Cancer Through K-Ras/PLC /PKC Signaling Pathway KRAS mutation G12C, inhibitor 9, castration-resistant prostate cancer, drug resistance, metastasis Keywords: KRAS mutation G12C; inhibitor 9; castration-resistant prostate cancer; drug resistance; metastasis EN KRAS mutation G12C inhibitor 9 castration-resistant prostate cancer drug resistance metastasis 1 1 1 06/05/21 20210531 NES 210531 Please find the retraction statement below: Following publication, concerns were raised regarding image manipulation and duplication. [Extracted from the article]