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Pathology & Laboratory Medicine
Non–small cell lung cancer (NSCLC) remains one of the most common of all subtypes, accounting for approximately 85% of total lung cancer diagnoses.1,2 Yet despite its prevalence, it remains one of the most difficult to treat.
Of the estimated 230,000 patients who will receive an NSCLC diagnosis this year, nearly 60% will die.3 Treatment outcomes and overall survival rates remain poor, with NSCLC carrying a 5-year survival rate of just 6%.4 Yet the continued exploration of numerous biomarkers brings hope, and KRAS G12C has emerged as a potential actionable target.
In a recent webinar, Dr Mark Kruzel, MD, MBA, associate medical director, oncology at Quest Diagnostics, discussed the evolving biomarker landscape for KRAS G12C and offered updates on available testing methods and clinical guidance.
Unpacking the many biomarkers involved with NSCLC
Biomarkers have become the foundation for precision oncology treatments aimed at improving outcomes for NSCLC patients. “However, because NSCLC is a heterogenous disease, there are many actionable biomarkers,” Dr Kruzel says. These include EGFR, ALK rearrangements, NTRK fusions, and PD-L1 expression.
KRAS is the most prevalent and common biomarker found within lung cancer. “In normal cells, KRAS serves as the on-and-off switch for cellular proliferation,” Dr Kruzel says. “However, in its mutated and altered state, KRAS tends to favor the active form, particular KRAS G12C, thereby supporting tumorigenesis and sending signals downstream to promote cell proliferation and differentiation.”
KRAS G12C accounts for nearly half of all KRAS mutations in NSCLC.5 One in 8 of all NSCLC patients have the KRAS G12C mutation, which is comparable to the prevalence of EGFR mutations.6,7
Understanding the potential of KRAS G12C as a therapeutic target
“Despite nearly 4 decades of scientific efforts, targeting KRAS remains one of cancer’s toughest challenges,” Dr Kruzel says. Three reasons why:
- KRAS proteins lack surface pockets, which makes the tight binding of small molecules difficult8
- Their competitive inhibition is challenging due to the high affinity binding of GTP to KRAS9
- Nonselective binding to wild-type KRAS can inhibit wild-type KRAS and adversely affect the normal signaling of cells10
Regardless of the above challenges, innovation and years of research have revealed these 3 unique features that help make KRAS—and, in particular, KRAS G12C—a therapeutic target:
- Cysteine 12, which may allow for potential irreversible covalent binding11
- P2 Pocket, which is present in the inactive, GDP-bound form of KRAS and provides a potential binding site for small molecules12,13
- H95 Residue, which may provide a site to stabilize drug-protein interaction14
How will these findings affect the potential of precision medicine solutions for NSCLC? “Targeted inhibitors could selectively lock the KRAS G12C mutant protein in the inactive state, thereby locking the oncogenic signaling without affecting wild-type KRAS signaling,” Dr Kruzel says.
Finding KRAS G12C: molecular testing methodologies and guidelines
All professional cancer-related regulatory bodies—including the College of American Pathologists, American Society of Clinical Oncology, and the National Comprehensive Cancer Network®—recommend testing for KRAS G12C. Reporting guidelines have been designed to help with interpretation and guidance on therapy selection.
Both tissue biopsies and liquid biopsies are appropriate, as are single- and muti-gene platforms. While tissue biopsies remain the gold standard for detecting KRAS G12C, liquid biopsy is becoming more commonly and frequently used. “Liquid biopsy should be reserved for patients who are most seriously ill, require a rapid result, and for those in which the tissue specimen was insufficient,” Dr Kruzel says.
Solving the puzzle of NSCLC
While NSCLC remains a difficult condition to diagnose and treat in its earliest stages, immunotherapy has improved overall survival in a subset of patients who respond to these treatments.15,16
“Inhibitors of KRAS G12C that block oncogenic signaling represent an important therapeutic approach in NSCLC,” Dr Kruzel says. “For this reason, molecular characterization of NSCLC through biomarker testing—including testing for emerging biomarkers like KRAS G12C—is essential.”
- National Cancer Institute. Accessed May 25, 2023. https://seer.cancer.gov/statfacts/html/lungb.html.
- American Cancer Society. Accessed May 25, 2023. https://www.cancer.org/cancer/types/lung-cancer.html.
- National Cancer Institute. Accessed May 25, 2023. https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq.
- National Cancer Institute. Accessed May 25, 2023. https://seer.cancer.gov/archive/csr/1975_2015/results_merged/topic_survival.pdf.
- Arbour KC, Rizvi H, Plodkowski AJ, et al. Treatment outcomes and clinical characteristics of patients with KRAS-G12C-mutant non–small cell lung cancer. Clin Cancer Res. 2021;27(8):2209-2215. doi:10.1158/1078-0432.CCR-20-4023
- Data on file. Amgen. 2020.
- Ahmadzada T, Kao S, Reid G, Boyer M, Mahar A, Cooper WA. An update on predictive biomarkers for treatment selection in non–small cell lung cancer. J Clin Med. 2018;7(6):153. Published 2018 Jun 15. doi:10.3390/jcm7060153.
- Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13(11):828-851. doi:10.1038/nrd4389
- Ryan MB, Coker O, Sorokin A, et al. KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy. Cell Rep. 2022;39(12):110993. doi:10.1016/j.celrep.2022.110993.
- Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771-785. doi:10.1038/nrd.2016.139
- Lanman BA, et al. Presented at The Association for Cancer Research March 29–April 3, 2019, Atlanta, GA. Abstract 4455.
- Seiki AY, et al. Presented at The Association for Cancer Research March 29–April 3, 2019, Atlanta, GA. Abstract 4484.
- Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217-223. doi:10.1038/s41586-019-1694-1
- Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol. 2019;37(28):2518-2527. doi:10.1200/JCO.19.00934
- Antonia SJ, Borghaei H, Ramalingam SS, et al. Four-year survival with nivolumab in patients with previously treated advanced non–small-cell lung cancer: a pooled analysis. Lancet Oncol. 2019;20(10):1395-1408. doi:10.1016/S1470-2045(19)30407-3