Collaboration Accelerates KRAS Inhibitor Development

Pasi A. Jänne, MD, PhD

A novel first-in-class covalent KRAS inhibitor SML-8-73-1 has demonstrated promise in preclinical studies, prompting a 3-year research collaboration between the Dana-Farber Cancer Institute and Astellas Pharma Inc.

KRAS, the most commonly mutated oncogene, has been the focus of research for over 20 years without much success. Mutations in the hard to target gene are common in patients with lung cancer and pancreatic cancer, and generally denote a worse prognosis.

Over the course of the past decade, targeted therapies against the ALK translocation and EGFR mutation have transformed the treatment for many patients with non-small cell lung cancer (NSCLC), resulting in significant extensions in survival. However, KRAS mutations are non-overlapping with EGFR and ALK, leaving chemotherapy as the only approved option for these patients.

"This is a population of cancer patients for whom current therapeutic approaches are limited. We are excited at the opportunity to work collaboratively with Astellas in an effort to develop a new approach to treating KRAS-mutant cancers," Pasi A. Jänne, MD, PhD, the scientific director at the Belfer Institute for Applied Cancer Science at Dana-Farber Cancer Institute, said in a statement. "Our collective expertise in clinical need, basic biology, mouse models, and screening/medicinal chemistry should help make this a productive collaboration."

In a paper published by Nathanael Gray, PhD, et al earlier this year, the GDP analog SML-8-73-1 demonstrated promise in preclinical models at directly targeting oncogenic KRAS. In the study, treatment with SML-8-73-1 stabilized the inactive form of KRAS G12C and demonstrated the ability to effectively inhibit abhorrent KRAS signaling.

The novel agent is comprised of an electrophilic chloroacetamide attached to beta phosphate, which allows it to covalently modify cysteine 12 of KRAS G12C. The therapy is selective for tumors with a KRAS G12C mutation, which accounts for approximately 50% of RAS-driven lung adenocarcinomas and is most common in patients with a history of smoking.

"Our work opens up a new approach to developing KRAS inhibitors," said Gray, from the Dana-Farber Cancer Institute, who will be the lead researcher for the collaboration. "We are excited to work with a top-tier pharmaceutical company committed to innovative oncology research on this collaboration, and to develop novel inhibitors to this molecular target that have thus far been inaccessible."

Astellas made the decision to support research into the novel KRAS inhibitor, with the option to obtain an exclusive worldwide license. Innovation Management of Astellas will lead the collaboration.

"We are pursuing open innovation in drug discovery and are looking for new drug discovery opportunities that satisfy unmet medical needs through collaboration with external partners," Kenji Yasukawa, PhD, senior vice president and chief strategy officer at Astellas Pharma Inc, said in a statement. "This collaboration with Dana-Farber perfectly illustrates this strategy and it is our hope that this collaboration to advance drug discovery will bring innovative cancer treatments to patients around the world."

In addition to the direct inhibition of KRAS, MEK inhibition has demonstrated promise as a treatment for KRAS-mutant malignancies. A preclinical study demonstrated that cell lines of KRAS G12D-mutant NSCLC that exhibited either LKB1 loss, the TP53 subtype, or KRAS mutation alone, were amenable to treatment with docetaxel plus the MEK inhibitor selumetinib.

In a trial that looked at chemotherapy with or without selumetinib in stage IIIB to IV KRAS-mutant NSCLC, progression-free survival (PFS) was 2.1 months with docetaxel and 5.3 months in the combination group. Response was 0% with chemotherapy alone and 37% with selumetinib. The median overall survival improved with selumetinib, from 5.3 to 9.4 months. Similar findings were seen with the combination of the MEK inhibitor trametinib with docetaxel, with an overall response rate of 28% in KRAS-mutated cancers in a phase II expansion study.