Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

Qiulin Tang,Gongmin Zhu,Lijiao Pei,Hongwei Xia,Feng Bi

doi:10.1186/s12943-021-01441-4

Abstract

Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

Highlights

Colorectal cancer (CRC) ranks third in terms of new cases and represents the second leading cause of cancer-related death worldwide in 2018 [1]
The upstream signal regulation of Kirsten rat sarcoma (KRAS) is interrupted by aberrant activation of the KRAS pathway, which results in resistance to receptor tyrosine kinase (RTK) inhibitors, such as monoclonal antibodies against epidermal growth factor receptor (EGFR), in patients with KRAS-mutant CRC [10, 11]
Recent studies have found that treatment of K RASG12C allele-specific inhibitors or SHP2 inhibitors, or mitogen-activated protein kinase kinase (MEK) inhibitors could activate anti-tumor immune cells and thereby relieve immunosuppressive status, which improves the response of KRAS-mutant CRC to immune checkpoint inhibitors in preclinical models [66, 87, 88, 130]. These results suggest that the combination of immune checkpoint inhibitors with these KRAS-targeted therapies is promising for the treatment of KRAS-mutant CRC, but the clinical efficacy of these combination therapies needs to validate in subsequent clinical trials

Summary

Introduction

Colorectal cancer (CRC) ranks third in terms of new cases and represents the second leading cause of cancer-related death worldwide in 2018 [1]. BI 1701963, a BI-3406 analogue, is being evaluated in a phase I clinical trial alone or in combination with trametinib in patients with advanced KRAS-mutant tumors (NCT04111458; Tables 2 and 3). RMC-4630 is in a phase I clinical trial as a single agent (NCT03634982; Table 2) and in a new clinical trial in combination with an ERK inhibitor, LY3214996, for the treatment of patients with metastatic KRAS-mutant cancers (NSCLC, CRC and pancreatic cancer) (NCT04916236; Table 3).

Results

Conclusion