Mutant oncogenes play a key role in driving cancer progression, and this fact has set the stage for the discovery of targeted anticancer therapies. The most successful example of using oncogene as a therapeutic target is protein kinase inhibitors, which offer clinical benefits in a broad range of cancer types.
KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) gene is a proto-oncogene that encodes a small GTPase transductor protein called KRAS. The mutant KRAS protein is one of the most common drivers in cancer.
The oncogene KRAS is activated in a third of cancers; however, there are no approved therapies that target this gene. This article provides a snapshot of past and ongoing efforts to target KRAS signaling in cancer therapy. We then focus on the KRAS inhibitors in clinical development.
KRAS works as a molecular switch
KRAS, a member of the Ras family, is a signal transducer protein that plays a vital role in controlling several cellular signaling pathways that regulates normal cellular proliferation.
KRAS cycles between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states. KRAS can bind and activate its effector proteins only in the GTP-bound state.
Wild‐type KRAS exists mostly in an inactive state in non‐dividing cells, whereas mutant KRAS interferes with the cycling process and is continuously in a GTP‐bound, active state. Mutant KRAS proteins locked in active state results in constitutive stimulation of effector pathways and drive tumor development.
Targeting KRAS signaling in cancer therapy - Drugging the 'undruggable'
For a long time, KRAS was considered an undruggable oncoprotein. As a result, the focus shifted on alternate approaches, such as inhibiting signaling cascades downstream of RAS, particularly the MAPK and PI3K pathways.
Targeting KRAS pharmacologically has been challenging due to its high affinity for GTP/GDP and the lack of a clear binding pocket to which small molecules can bind. However, recent developments in basic and translational research have led to the discovery of a previously unknown drug-binding pocket on the surface of KRAS. This discovery aroused interest in developing innovative strategies to develop KRAS targeted anticancer drugs.
The novel strategies explored include covalently targeting mutant KRAS, inhibiting KRAS interaction with associated proteins required for membrane association, inhibiting KRAS-driven malignant phenotypes, and KRAS synthetic lethal interactions.
The decades-long dream of 'drugging' KRAS is now a reality - KRASG12C inhibitors are now entering clinical trials
KRAS-activating mutations are the most frequent oncogenic alterations in human cancer. Among the mutations, KRASG12C is present in 13% of lung adenocarcinomas, 3% of colorectal cancers, and 2% of other solid tumors.
After a long struggle, there is finally some hope as many KRAS targeted therapies are being developed, with few on the verge of approval.
Advances in research has led to the development of promising KRasG12C inhibitors that covalently bind to the mutated cysteine residue in the switch-II pocket and lock the protein in the inactive GDP-bound state.
KRAS inhibitors in development
The identification of KRASG12C inhibitors represents a new hope for patients suffering from KRasG12C driven cancer.
The decades-long quest for therapeutic strategies targeting oncogenic RAS-driven cancers has now reached a major milestone. In the past few years, compounds that covalently bind to KRASG12C at the cysteine 12 residue and lock the protein in its inactive GDP-bound conformation have been identified. These co...
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