Movers and SHAKERS
Does the recent RAS inhibitor data show that we can effectively treat RAS-related cancers?
(Note: companies that could be impacted by the content of this article are listed at the base of the story [desktop version]. This article uses third-party references to provide a bullish, bearish, and balanced point of view; sources are listed after the Balanced section.)
The RAS pathway is one of the most frequently dysregulated pathways in cancer. Approximately 30% of tumors harbor activating RAS gene mutations. There are three main isoforms of oncogenic RAS: KRAS, HRAS and NRAS. Among these genes, KRAS is the most frequently mutated (90% of pancreatic cancers, 35% of colon cancers). In comparison, NRAS and HRAS are mutated in a lesser number of cancer patients (for example, 15% of melanomas and 4% of head and neck cancer patients carry mutations in NRAS and HRAS, respectively).
The RAS protein family consists of low molecular weight guanosine 5-triphosphate (GTP, the building block of protein synthesis)-binding proteins that orchestrate a variety of cellular signaling networks. These pathways or networks are essential to regulate a variety of cellular functions including cell proliferation, differentiation, and cell survival. The three RAS proteins (N-RAS, H-RAS and K-RAS) oscillate between an active (GTP-bound) and an inactive (GDP-bound) state. When RAS genes are mutated (typically at codon 12, 13 or 61), RAS proteins are constitutively activated (continuously binding to GTP), which induces a pro-tumorigenic state characterized by unregulated cell proliferation and resistance to apoptosis (evading death signals). Constitutively activated RAS proteins trigger downstream signaling responsible for phenotypic traits known as hallmarks of cancer including: i) aberrant cell proliferation, ii) resistance to apoptosis (evasion of death signals), iii) increase in migration, cell invasion and metastasis to different tissues and iv) escaping the anti-tumoral immune response. The phenotype of many cancer cells is determined by RAS-dependent aberrant signal transduction pathways involving various oncogenic proteins acting downstream of RAS (Exhibit 1).
Exhibit 1. RAS signaling pathways involved in human cancer
Source: Seminars in Cancer Biology 54 (2019) 138–148
RAS is an important therapeutic target, but is it a druggable target?
The high mutational rate of RAS genes in cancer patients, combined with the fundamental role of RAS proteins in cancer biology, makes the RAS family of oncoproteins a primary therapeutic target. Since its discovery in 1982, both academia and industry have made significant efforts to develop an anti-cancer medicine targeting RAS. Despite these intensive efforts, there are no FDA approved anti-RAS drugs at present. Multiple clinical failures have led to the general perception that the oncogene RAS is “undruggable”.
BULL: Drugging the Undruggable – Promise of Winning the War Against RAS Oncoproteins
The clinical data readout from Amgen (AMGN)’s KRAS G12C inhibitor showed promising clinical benefit in lung cancer. AMG-510 is a first in class KRAS G12C inhibitor, that is currently being assessed in Phase 1/2 clinical trial (NCT 03600883) to treat adult patients with locally advanced or metastatic solid tumors carrying the KRAS G12C mutation. The new data from this ongoing Phase 1 study was announced at the European Society for Medical Oncology (ESMO) 2019 Congress in September 2019. Among a subset of 55 evaluable patients, 29 were diagnosed with colorectal cancer (CRC), 23 with non-small cell lung cancer (NSCLC) and 3 with other tumor types. Patients with NSCLC showed the most favorable results; 11 (48%) patients achieved a partial response (PR), 11 (48%) had stable disease (SD) and 1 (4%) had progressive disease (PD). AMG-510 showed a modest clinical benefit in patients with CRC, 1 (3%) achieved PR and 22 (76%) patients achieved SD whereas 1 (21%) had PD.
Interim data from Mirati (MRTX)’s KRAS G12C program also showed early promise. Mirati Therapeutics, Inc. (MRTX) presented the first results from its Phase 1/2 clinical trial evaluating MRTX849 (an investigational KRAS G12C inhibitor) in patients with solid tumors expressing KRAS G12C mutations at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Conference. MRTX849 demonstrated clinical activity (PR) in 3 (50%) of the six patients with NSCLC, 1 (25%) of four patients with CRC. The interim data analysis from MRTX849 program demonstrated the second early signal of clinical benefit in patients harboring KRAS G12C mutations following AMG-510.
Other pharmaceuticals are also joining the RAS battle. These positive developments in the KRAS field has inspired additional collaboration and R&D efforts. The first news came in July 2019 from Novartis (NVS) that teamed up with Mirati. Two companies will evaluate KRAS G12C inhibitor (MRTX849) and an investigational SHP2 (TNO155) inhibitor in patients with advanced solid tumors that harbor KRAS G12C mutations. The second news came from Boehringer Ingelheim (Private) that plans to advance its KRAS inhibitor BI 1701963 to Phase I clinical testing alone and in combination with trametinib (MEK inhibitor) in patients with different types of advanced solid tumors with KRAS mutations.
BEAR: Quest for the Holy Grail?
Complex signaling pathway of RAS. Due to the high level of interaction and crosstalk within the cellular signal transduction network, prior efforts to target RAS signaling in the clinics have failed. In cancer, the RAS pathway can become activated by aberrations in upstream growth factor receptors, downstream pathway proteins, by loss of function of RAS negative regulators, and through activation of alternative pathways. The complex nature of RAS pathways and their interactions with multiple downstream enzymes represents a significant challenge for drug developers.
Lack of binding pockets and high affinity to its substrate (GTP/GDP) made RAS undruggable. The RAS proteins have relatively featureless (lack of binding pockets), almost perfect spherical structures. This has made it very challenging to develop a compound that can bind and inhibit RAS activity. Although, recent developments have shown promising result targeting KRAS G12, other mutations (G12V, G12D, G13D, Q61N) and isoforms (HRAS and NRAS) that occurs in high rate remain undruggable.
Previous multiple failures in the RAS field. The search for an effective RAS inhibitor for the treatment of cancer has been as elusive as the famous “Quest for the Holy Grail” described in Arthurian literature. One of the most recent disappointments in this field took place in April 2019. An anti-KRAS antisense oligonucleotide AZD4785 was developed to target the protein regardless of its mutation status. The AZD4785 program was discontinued after falling short to demonstrate favorable response rates in a Phase 1 trial to treat patients with NSCLC and solid tumors. It is important to note that AZD4785, unlike AMG-510 and MRTX1257, did not specifically target G12C mutated RAS.
BALANCE: Bringing the holy grail of cancer research within reach
RAS is the most commonly mutated oncogene in cancer (approximately 30% of cancer patients carry genetic mutations in RAS oncogenes). The RAS signal transduction network is large and complex and consists of many interconnecting pathways that play a major role in cellular growth, evasion of apoptosis, and metastasis. Efforts to develop anti-cancer drugs targeting RAS have contributed greatly to the understanding of RAS function, biology, and signaling pathways. The recent discovery of novel RAS inhibitors with sufficient affinity and selectivity for mutant forms of RAS have demonstrated promise as potential cancer treatments. Further research will continue to improve our understanding of the RAS signaling network and shed light on new therapeutic strategies. In the near future, new approaches and technologies may finally bring the holy grail of cancer research within reach, converting RAS-oncoproteins from an “undruggable” target into a “druggable” one.
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