Mechanisms of resistance to direct KRAS G12C inhibition

2020

Kathryn Arbour, MD

Memorial Sloan Kettering Cancer Center

New York

Dr. Arbour will test a combination treatment regimen (MRTX849 for KRAS G12C and TNO155 for SHP2) in specialized mouse models of KRAS-mutant lung cancer, as well as analyze blood samples from patients who are currently receiving the MRTX849 drug to proactively monitor how these patients are developing resistance to MRTX849. Her ultimate goal is for new drugs, such as TNO155, to be added to the treatment regimen for KRAS-positive patients to combat acquired resistance. Dr. Arbour is the recipient of the Kristie Rolke Smith/LUNGevity Career Development Award, generously funded by the Rolke family in memory of their daughter, Kristie.

Research Summary

Despite advancements in lung cancer detection and new therapies, lung cancer remains the most common cause of cancer death in the United States. Over the past decade, the identification of molecular drivers of lung cancer has revolutionized treatment through development of more personalized and effective therapies. Mutations in KRAS, one such driver oncogene, are identified in 25-30% of cases of lung adenocarcinoma. While molecularly targeted therapies have proven effective for other driver oncogenes, such as EGFR and ALK, the clinical activity of molecularly targeted therapy in KRAS mutant lung cancer has been limited as KRAS was long considered an “undruggable” target. Prior efforts focused on targeting downstream signaling pathways were largely ineffective. KRAS G12C mutations are the most common subtype in lung adenocarcinoma and are present in 12% of lung cancer patients overall. In 2013, the identification of the binding pocket of the KRAS G12C protein enabled the development of direct inhibitors, a significant breakthrough for the field. In early phase clinical trials this new class of agents has demonstrated efficacy with 40-50% of patients having substantial tumor shrinkage, representing another major advance for the field. While treatment can lead to tumor regression, nearly all patients have less than maximal responses and are likely to develop acquired resistance. Combinations of molecularly targeted therapy may result in deeper and more durable responses resulting in improved outcomes for patients with KRAS G12C mutant lung cancer.

Technical Abstract

KRAS mutations are the most common activating mutation in lung cancer and are identified in 25-30% of cases of lung adenocarcinoma. The clinical activity of molecularly targeted therapy in KRAS mutant lung cancer has been limited, as most prior approaches focused on downstream targets of the MAPK pathway, an approach which was largely ineffective. KRAS G12C is the most common subtype of activating KRAS mutation in NSCLC. Identification of a binding pocket of KRAS G12C enabled the development of covalent inhibitors (Ostrem et al. Nature, 2013), which selectively bind to the mutant cysteine and spare wild type or other mutant KRAS proteins (hereafter referred to as G12Ci). These drugs bind only to GDP-bound (i.e. inactive) KRAS G12C and trap the oncoprotein in its inactive state by preventing nucleotide exchange (Lito et al. Science, 2016). Of this new class of agents, two drugs (MRTX849 and AMG510) have demonstrated efficacy in early phase clinical trials, representing a remarkable breakthrough in the management of KRAS G12C mutant lung cancer. Acknowledging the limited number of patients treated thus far, response rates of 40-50% have been reported, demonstrating clinical activity far superior to prior molecularly targeted approaches for the management of KRAS mutant lung cancer. Despite this major advance it is clear that resistance to therapy, both primary and acquired, will remain a challenge and may in part be due to upstream receptor tyrosine kinase (RTK) signaling. Understanding the mechanisms of resistance to this new class of therapy is of paramount importance to improve the efficacy and durability of response, and for identifying rational combinatorial therapies for future clinical trials.

Key words

Acquired resistance

Biomarker or biomarker testing

KRAS

Metastatic

Non-small cell lung cancer (NSCLC)

Stage III

Stage IV

Mechanisms of resistance to direct KRAS G12C inhibition

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