Targeting the undruggable oncogenic KRAS: the dawn of hope
Hande Asimgil, … , Güralp Onur Ceyhan, Ihsan Ekin Demir
Hande Asimgil, … , Güralp Onur Ceyhan, Ihsan Ekin Demir
Published January 11, 2022
Citation Information: JCI Insight. 2022;7(1):e153688. https://doi.org/10.1172/jci.insight.153688.
View: Text | PDF
Review

Targeting the undruggable oncogenic KRAS: the dawn of hope

Abstract

KRAS mutations are the drivers of various cancers, including non–small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts have been made to inhibit KRAS mutants and oncogenic KRAS signaling using inhibitors. Recently, specific targeting of KRAS mutants with small molecules revived the hopes for successful therapies for lung, pancreatic, and colorectal cancer patients. Moreover, advances in gene editing, protein engineering, and drug delivery formulations have revolutionized cancer therapy regimens. New therapies aim to improve immune surveillance and enhance antitumor immunity by precisely targeting cancer cells harboring oncogenic KRAS. Here, we review recent KRAS-targeting strategies, their therapeutic potential, and remaining challenges to overcome. We also highlight the potential synergistic effects of various combinatorial therapies in preclinical and clinical trials.

Authors

Hande Asimgil, Utku Ertetik, Nedim Can Çevik, Menar Ekizce, Alper Doğruöz, Muazzez Gökalp, Elif Arık-Sever, Rouzanna Istvanffy, Helmut Friess, Güralp Onur Ceyhan, Ihsan Ekin Demir

×

Figure 2

Immunotherapy regimens for the treatment of oncogenic KRAS–driven tumors.

Options: View larger image (or click on image) Download as PowerPoint
Immunotherapy regimens for the treatment of oncogenic KRAS–driven tumors...
(A) Vaccines that promote oncogenic KRAS antitumor immunity. Peptide-, mRNA-, and DC-based vaccines can be administered to patients with lung, pancreatic, and colon cancer. Vaccines provide oncogenic KRAS neoantigens to MHC molecules and aim to develop cancer-specific long-term memory T cells. Upon tumor growth, activated T cells destroy cancerous cells through TCR-MHC binding. (B) Adoptive cell therapy with engineered T and NK cells. T and NK cells isolated from a patient’s blood are genetically modified by viral vectors to express specific T cell receptors (TCRs) and neoantigen specific NK receptors for a better recognition of oncogenic KRAS–expressing cancerous cells. Peripheral blood T cells from patients with lung, pancreatic, and colon cancer are alternatively used to create CAR-T and CAR-NK cells that express patient-specific, KRAS-driven cancer cell neoantigens. (C) After surgical resection of a tumor, patient-specific tumor-resident active T cells (TILs) are isolated and expanded and selected ex vivo. The most tumor-specific and functionally enriched T cells are administered to the patient intravenously after lymphodepletion.