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 compounds inhibit KRAS-dependent signaling and trigger anti-tumor responses.

Amgen and Mirati Therapeutics – The frontrunners

Amgen and Mirati Therapeutics Amgen and Mirati Therapeutics recently unveiled two different KRASG12C inhibitors— Sotorasib (AMG 510) and Adagrasib (MRTX849). Both the compounds have demonstrated striking in vivo anti-tumor effects in mice and clinical activity in people with lung and colon adenocarcinomas. Indeed, there are many medical supplies companies and surgical supply companies have been working on KRASG12C inhibitors.

Both the inhibitors work by covalently attaching to the mutant Cys residue in KRASG12C. Notably, these inhibitors only target mutant RAS in the GDP-bound state, thereby locking the protein in the inactive conformation and blocking the oncogenic signaling.

Amgen's Sotorasib has received breakthrough therapy designation

Sotorasib is the first KRASG12C inhibitor to enter the clinic. Sotorasib recently received breakthrough therapy designation from the FDA.

In January 2021, Amgen announced results from the Phase 2 cohort of the CodeBreaK 100 study. The CodeBreaK 100 study evaluated Sotorasib in 126 patients with KRAS G12C-mutated advanced NSCLC.

Sotorasib demonstrated a confirmed objective response rate (ORR) and disease control rate (DCR) of 37.1% and 80.6%, respectively, and a median duration of response of 10 months (data cutoff of Dec.1, 2020; median follow-up time was 12.2 months).

Sotorasib is also the first KRASG12C inhibitor to show progression-free survival (median of 6.8 months) in a Phase 2 study, which is consistent with earlier Phase 1 results in previously treated patients with KRAS G12C-mutated advanced NSCLC.

Adagrasib 

Mirati Therapeutics' oral KRAS inhibitor, Adagrasib (MRTX849), has shown promise in early clinical trials.

The phase I/Ib part of KRYSTAL-1 enrolled 110 patients with the KRAS G12C mutation and previously treated advanced NSCLC, colorectal cancer, and other solid tumors (pancreatic, ovarian, endometrial, cholangiocarcinoma). 

Seventy-nine patients with NSCLC in the phase I/II group were treated with Adagrasib monotherapy at 600 mg orally twice a day. The study reported confirmed objective responses in 45% and a disease control rate of 96% in 51 evaluable patients in phase II followed for a median of 3.6 months. 

In 31 patients with colorectal cancer and other solid tumors, of the 18 evaluable patients, 3 (17%) had a confirmed response. Disease control was achieved by 17 (94%). 

Researchers are also planning to evaluate adagrasib in combination with other targeted therapies, such as cetuximab for colon cancer and afatinib or pembrolizumab for NSCLC. 

Conclusion

The ability to personalize cancer therapy by targeting driver mutations has caused a paradigm shift in lung cancer treatment.

The impressive early clinical data for both Sotorasib and Adagrasib mark the beginning of a new era in treating patients with KRASG12C alterations. These breakthroughs have broad implications for future targeting efforts as the unsolvable puzzle of 'drugging' KRAS is now solved.

References

1.    Pantsar T. The current understanding of KRAS protein structure and dynamics. Comput Struct Biotechnol J. 2019;18:189-198. Published 2019 Dec 26. doi:10.1016/j.csbj.2019.12.004

2.    Amgen's Investigational KRAS G12C Inhibitor Sotorasib Demonstrated Rapid, Deep And Durable Responses In Previously Treated Patients With Advanced Non-Small Cell Lung Cancer. Available at: https://www.amgen.com/newsroom/press-releases/2021/01/amgens-investigational-kras-g12c-inhibitor-sotorasib-demonstrated-rapid-deep-and-durable-responses-in-previously-treated-patients-with-advanced-nonsmall-cell-lung-cancer Accessed on: 07Mar2021.

3.    Zuberi M, Khan I, O'Bryan JP. Inhibition of RAS: proven and potential vulnerabilities. Biochem Soc Trans. 2020;48(5):1831-1841. doi:10.1042/BST20190023

4.    KRAS Inhibitor Adagrasib Shows Activity in Non–Small Cell Lung Cancer . ASCO post. Nov 2020. Available at: https://ascopost.com/issues/november-25-2020/kras-inhibitor-adagrasib-shows-activity-in-non-small-cell-lung-cancer/. Accessed on: 07Mar2021.

About the Author:

Neeta Ratanghayra 

a freelance medical writer, who creates quality medical content for Pharma and healthcare industries. A Master’s degree in Pharmacy and a strong passion for writing made her venture into the world of medical writing. She believes that effective content forms the media through which innovations and developments in pharma/healthcare can be communicated to the world."