Emergence of KRAS mutations and acquired resistance to anti EGFR therapy in colorectal cancer

By S. Misale, R. Yaeger, S. Hobor, E. Scala, M. Janakiraman, D. Liska, E. Valtorta, R. Schiavo, M. Buscarino, G. Siravegna and 16 more. Nature, 2012

1,835 citations recorded by the source corpus.

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

Subfields: Oncology, Pathology and Forensic Medicine, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/e2b86912eb8dc9cedca4de64958335375dca4e1d

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In Oncology

1. Nicholas McGranahan
2. Charles Swanton
3. A. Marusyk
4. K. Polyak
5. Fortunato Ciardiello
6. Carlos L. Arteaga
7. J. Engelman
8. R. Weinberg

In Pathology and Forensic Medicine

1. Carlos L. Arteaga
2. A. Bardelli
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In Pulmonary and Respiratory Medicine

1. Carlos L. Arteaga
2. Charles Swanton
3. Nicholas McGranahan
4. J. Engelman

Citations in the corpus

• Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations (2018, background): “In solid tumours, subclonal drug-resistance mutations are similarly relevant but may be missed by physical biopsy 130 .”
• Origins, structures, and functions of circulating DNA in oncology (2016, background): “Non-invasive analysis of acquired resistance to cancer therapy by analyzing plasma DNAwas later demonstrated in breast and colorectal patients [75, 235, 238].”
• Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “, 2013), colon (Misale et al., 2012; Siravegna et al., 2015), and lung (Anagnostou et al.”
• ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics (2014, background): “…such as molecular interrogation of circulating tumor cells or plasma DNA may help capture the heterogeneity of resistance in patients, as was done to identify the development ofKRASmutations in colorectal cancers that acquire resistance to cetuximab (Diaz et al., 2012; Misale et al., 2012).”
• Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, positive): “In several cancer types (Alexandrov et al., 2013), a phenomenon termed kataegis has been observed; describing a small localized mutational process that results in hyper-mutation (a few to several hundred C>T and/or C>G substitutions, enriched at TpC sites) on the same DNA strand.”
• Liquid Biopsies: Genotyping Circulating Tumor DNA (2014, background): “In this case, the discovery of the mechanisms of resistance to the targeted agent was simultaneously accomplished in tissue and liquid biopsies.(60,65) Another noteworthy aspect of these studies was the emergence of multiple different resistance mutations in the same patient.”