MAPK-pathway alterations are associated with resistance to anti-HER2 therapy

Genomic analysis of HER2-positive breast tumours identified pathways alterations associated with anti-HER2 resistance and new therapeutic vulnerabilities.

Resistance to anti-human epidermal growth factor receptor 2 (HER2)-therapy is common and more insight in the molecular pathways involved, could lead to new treatment strategies. Previous research demonstrated the involvement of alterations in the PI3K-pathway in resistance to anti-HER2 therapy [1,2].

To explore the role of the mitogen-activated protein kinase (MAPK)-pathway in anti-HER2 resistance, Dr Emanuela Ferraro (Memorial Sloan-Kettering Cancer Center, NY, USA) and colleagues performed next generation sequencing on 733 HER2-amplified tumours (385 primary, 348 metastatic) from patients with advanced HER2-positive breast cancer. Frequency of MAPK-pathway alterations was 9.8% in primary tumours and 15.6% in metastatic tumours [3,4]. Of note: frequency of PI3K-pathway alterations were 30.6% and 37.3%, respectively. Both PI3K-pathway alterations (mutant 13 months vs wildtype 23 months; P=0.0013) and MAPK-pathway alterations (mutant 9.9 months versus wildtype 21 months; P=0.01, see Figure) were associated with a statistically significant worse clinical outcome for progression-free survival. MAPK-pathway alterations were also independently associated with worse outcome after correction for PIK3CA mutations, ERBB2 amplification, and oestrogen-receptor status (HR 2.24; P=0.0039). The causal involvement of MAPK-pathway in HER2-resistance was confirmed in additional in vitro studies, where MAPK-altered cell lines showed resistance to FDA approved HER2-inhibitors. In addition, HER2-resistant cell lines proved to be sensitive for MEK inhibitors.

Figure: Progression-free survival stratified by MAPK-pathway alteration [3,4].



 

 

 

 

 

 

 

MAPK, mitogen-activated protein kinase; WT, wildtype; PFS, progression-free survival; HR, hazard ratio.

Reprinted and modified from Smith AE, et al. Nat Commun. 2021;12(1):6667 Doi.org/10.1038/s41467-021-27093-y under the terms of the Creative Commons Attribution 4.0 license.

“Our analysis uniquely identified MAPK-pathway alterations as additional potential drivers of resistance to anti-HER2 therapy. Inhibition of the PI3K or MAPK-pathway in such tumours may represent a new therapeutic strategy to extend the anti-HER2 benefit,” concluded Dr Ferraro.

1. Berns K, et al. Cancer Cell. 2007;12:395–402.
2. Baselga J, et al. J Clin Oncol. 2014;32:3753–3761.
3. Ferraro E, et al. Genomic analysis of 733 HER2+ breast cancers identifies recurrent pathways alterations associated with anti-HER2 resistance and new therapeutic vulnerabilities. GS3-03, SABCS 2021 Virtual Meeting, 7–10 December.
4. Smith AE, et al. Nat Commun. 2021;12(1):6667.

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Posted on 31 January 202223 April 2024