Story Topic: KRAS

Addressing unmet needs in the oncology space can be challenging, but our team of scientists embraces the challenge with persistence and commitment. For many of us, this commitment has been intrinsically motivated by walking alongside a loved one’s cancer journey. With 1.9 million new cancer diagnoses expected in the US this year¹, there is a huge need and significant potential to impact a large population through a wide range of targeted therapeutics. I’m confident the experience, knowledge and commitment of our team can have a meaningful impact to improve the lives of those living with cancer.

With 1.9 million new cancer diagnoses expected in the US this year¹, there is a huge need and significant potential to impact a large population through a wide range of targeted therapeutics.

Our cutting-edge scientific innovation, combined with our dedication to improving patients’ lives, has allowed us to deepen our pipeline of targeted oncology therapies. By investigating the genetic and immunological drivers of cancer, we are seeing great opportunities to create meaningful impact with our late-stage and near-launch programs. The positive results seen recently in two groups of patients – those with previously treated NSCLC harboring a KRAS^G12C mutation and patients with KRAS^G12C-mutated NSCLC with active and untreated CNS metastases – highlight Mirati’s potential to positively impact patients living with cancer. Recent data presented at the European Society for Medial Oncology Congress 2022 points to our dedication to developing safe treatment options for other solid tumors, including colorectal cancer, that improve upon the standard of care as well.

With Mirati’s discovery programs, we are also developing and exploring the applications of other therapies, like our MTA-cooperative PRMT5, SOS1 and next-generation KRAS inhibitors. These treatments have the potential to be transformative for a wide range of cancer patients, and I’m eager to see these programs continue to advance.

As we approach the end of the year, I’m proud of the progress Mirati has made toward delivering innovative cancer treatment options. And, I’m especially excited about our potential to create medicines that can impact cancer across mutation and tumor types, and even complement other agents in our pipeline to create greater impact. We have established our marketing strategy, market access, patient support and medical affairs capabilities, and now, we have in place all the components necessary to successfully deliver this innovation to the patients in need.

I’m excited at the future for Mirati and what it holds for patients and their loved ones, and I’m grateful to our team for their relentless pursuit to make a difference for people living with cancer.

1. Cancer Facts & Figures 2022

Mirati is striving to bring cutting edge science to the forefront. At this year’s meeting, among other research, we are proud to present our first clinical data set on central nervous system (or CNS) activity in patients with NSCLC harboring a KRAS^G12C mutation. This is important because CNS metastases can occur in up to 42% of patients with non-small cell lung cancer harboring the KRAS^G12C mutation, and often contribute or lead to death, posing a serious clinical challenge. I’m energized by what our team is doing to address this significant unmet medical need.

Most importantly, we want to thank the patients and physicians who make the research possible. I’m grateful to the dedicated Mirati Team who remain relentless in their pursuit of helping people living with cancer, who are counting on us to make a difference in their lives.

Follow Mirati’s LinkedIn company page for updates and perspective on our science during the 2022 ASCO Annual Meeting.

Sometimes however, a mutation can occur in one of these “genomic guardian” genes that partially degrades the cell’s ability to repair mutational damage. Such genes are sometimes called “tumor suppressor” genes because when they function normally, they prevent the development of tumors. Often, a mutation that inactivates one of these tumor suppressor genes is on the road to becoming a cancer cell, allowing the cell to accumulate more mutations in other genes, leading to the unrestrained growth and division that characterizes cancer. Cancer, then, can be thought of as a disease of genetic instability.

In recent years, with greater understanding of the many molecular events that result in the transformation of normal cells into cancer cells, therapies have been developed that target specific “driver” mutations. A good example is the G12C mutation in the KRAS gene – a key “on/off” switch that controls the circuitry of cell growth and division in response to cellular signals. While the normal KRAS protein can switch the circuit on and off depending on the signals it receives, mutations like G12C cause the protein to become stuck in the “on” position, constantly signaling the cell to replicate and grow. Cancers that are driven by the G12C mutation are a key focus for Mirati’s research. KRAS^G12C inhibitors can be thought of as the contrast to chemotherapy, and an example of personalized or precision medicine – a therapy designed to work only in the subset of cancers that have the KRAS^G12C mutation.

Many cancer driver mutations have been identified with most of them, which can be targeted, having newer generations of “precision” cancer medicines. However, there is another approach to precision or personalized medicine that also exploits the cancer cell’s genetic instability, while more efficiently sparing normal cells. Organisms often evolve redundancies in the metabolic pathways involved in critical functions (such as DNA damage repair) that if the function of one gene is lost, another can compensate and maintain cell viability.  In contrast, cancer cells develop inactivating mutations (or outright deletions) in one or more of these functionally redundant genes, rendering the tumor cell entirely dependent on the remaining “active” gene. By targeting the product of that last remaining gene, a drug can potentially be lethal to a cancer cell while sparing normal cells in which the “back-up” is still functional. This is the concept behind “synthetic lethality.”

The quintessential example of therapies designed to exploit synthetic lethality are the PARP inhibitors. PARP is an enzyme involved in the repair of single strand breaks in DNA. When PARP is inhibited, these single strand breaks accumulate and eventually become double-stranded breaks, affecting the DNA double helix. Cells with double-stranded breaks become dependent on other DNA damage repair pathways such as the homologous recombination pathway mediated by the tumor suppressor genes BRCA1 or BRCA2. Hence, breast, ovarian or prostate tumors with mutated BRCA genes are uniquely susceptible to PARP inhibitors as the combined inhibition of PARP with loss of BRCA activity eventually leading to catastrophic damage to the tumor DNA.

Another example of this synthetic lethality approach to cancer therapy is Mirati’s PRMT5 program. PRMT5 is a critical enzyme known as a “methyltransferase” that is involved in a host of essential cellular functions. Another enzyme called methylthioadenosine phosphorylase (MTAP) plays a critical role in methionine metabolism and is often missing in cancer cells because of its chromosomal location close to a commonly deleted tumor suppressor gene (CDKN2A).

Loss of MTAP in a cancer cell causes the accumulation of an intermediate called methythioadenosine, or ‘MTA.’ MTA is a partial inhibitor of PRMT5, therefore MTAP-deleted cells are profoundly sensitive to further inhibition of PRMT5 thereby setting up the context of vulnerability to synthetic lethality. This enhanced sensitivity to PRMT5 inhibition creates a large “therapeutic window,” in which doses of an inhibitor that are harmless to normal, MTAP positive cells, are lethal to MTAP-deleted cancer cells. Mirati’s PRMT5 inhibitor is designed to selectively bind PRMT5 in MTAP-deleted cancer cells in a novel way, and positioned to potentially have an improved therapeutic index based on the concept of synthetic lethality.

As is the case for inhibitors of G12C mutant KRAS tumors or PARP inhibitors in BRCA mutated cancers, a PRMT5 inhibitor drug is effective only in tumors with a homozygous MTAP deletion – which occurs in about 10 percent of all human cancers. This is another example of a ‘personalized’ or ‘precision’ approach to therapy that will only be active in an identifiable subset of cancer patients.

The promise of delivering on personalized medicine relies on suitable diagnostic tests (i.e. companion diagnostics) to identify patients who may benefit from targeted therapy. This is an important area of focus at Mirati and of the Translational Medicine team.