4bases’ paper of the month – October 2022 – “ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer”

Our team’s reading recommendation for this month is “ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer”, a very interesting paper conducted by RM Johnson et al. and recently published in “Nature Communications”. 

The majority of colorectal cancers (CRC) are caused by dysfunctions in signaling-pathways. Alterations in the genes involved in these pathways, such as EGFR/MAPK signaling, can lead to intrinsic (pre-existing baseline mutations) or acquired resistance (expansion of tumor clones with selective pressure mutations) to different treatments, such as treatments containing anti-EGFR or anti-VEGF. It should be noted that the latter two treatments mentioned have already shown an improved outcome in CRC patients. 

In this study, an analysis of circulating free DNA before and after treatment of the concerned patients showed acquired mutations in KRAS and ARID1A genes in patients treated with cetuximab (anti-EGFR) but not in patient treated with bevacizumab (anti-VEGF) containing therapy. The paper mainly focuses on the mutation in the so-called ARID1A regulator, which has also been shown to cause resistance to anti-EGFR-containing therapies besides KRAS. 

The paper presents two main findings. First, acquired mutations in ARID1A regulator are increasingly common in anti-EGFR therapies (e.g., cetuximab) but not in anti-VEGF therapies (e.g., bevacizumb). Moreover, patients presenting acquired mutations in ARID1A showed resistance to anti-EGFR therapies. This resistance was independent of the presence of mutations in KRAS or other alterations known to result in resistance to cetuximab therapy. This means that ARID1A-selected mutations can independently cause resistance to anti-EGFR therapy. Second, the authors found that, like acquired mutations in ARID1A, intrinsic mutations in ARID1A resulted in resistance to anti-EGFR therapies as well. Indeed, a comparison of outcomes between anti-VEGF and anti-EGFR therapies in patients presenting intrinsic mutations in ARID1A showed a poorer outcome of anti-EGFR therapies, while the two treatments had similar outcomes in ARID1A wild type patients.

ARID1A being part of the SWI/SNF chromatin remodeling complex, mutations therein have been shown to deregulate and impact gene transcription. The appearance of these mutations in cetuximab-treated patients indicates a functional link between EGFR signaling and ARID1A/SWI/SNF effectors in CRC patients that was previously undiscovered. In fact, the ARID1A/SWI/SNF complex negatively modulates transcription of EGFR downstream effectors which are known to promote sensitivity to anti-EGFR therapies. 

These results show that the ARID1A regulator mutation could potentially be used for therapeutic decision making and could potentially exclude patients from cetuximab treatment. This may also justify exploring therapeutic MAPK inhibition instead of EGFR inhibition in CRC patients.

Johnson RM, Qu X, Lin CF, Huw LY, Venkatanarayan A, Sokol E, Ou FS, Ihuegbu N, Zill OA, Kabbarah O, Wang L, Bourgon R, de Sousa E Melo F, Bolen C, Daemen A, Venook AP, Innocenti F, Lenz HJ, Bais C. ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer. Nat Commun. 2022 Sep 19;13(1):5478. doi: 10.1038/s41467-022-33172-5. PMID: 36117191; PMCID: PMC9482920.


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