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.

Figure 1. RNAi and CRISPR technology for treatment of oncogenic KRAS–driven cancers.

(A) Mutant KRAS–specific (mKRAS-specific) siRNAs and shRNAs silence the expression of mKRAS by generating an RNA hybrid complex that induces endogenous KRAS mRNA degradation. Inhibitory RNA molecules are encapsulated in a liposome, exosome, or nanoparticle and can be administered to patients via intravenous injection or orthotopic injections for access to oncogenic KRAS–driven tumor sites. Alternatively, adeno-associated viral (AAV) vectors may be used to intravenously deliver mKRAS-targeting therapeutics. Despite major safety concerns, viral vector delivery systems (adenoviral, retroviral, and lentiviral vectors) provide longer-lasting effects on RAS hotspot mutations. (B) Viral delivery of CRISPR/Cas9 (DNA) or Cas13 (RNA) systems that target mKRAS-expressing tumor cells is administered to the tumoral site via orthotopic injection. Through administration of KRAS sgRNAs in the CRISPR/Cas13 system, only transient correction of cancer cells at the post-transcriptional level can be attained. By directly targeting mKRAS, both RNAi- and CRISPR-based therapeutics promote tumor reduction.

Figure 2. 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.