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  • Among the HER mutations reported in

    2022-07-01

    Among the HER2 mutations reported in this study, the JMD mutant R678Q is the third most recurrent HER2 mutation. Basic residues (such as arginine) play an important role in anchoring TMD helices of single transmembrane proteins to the bilayer (Gleason et al., 2013, Hristova and Wimley, 2011, Kim et al., 2011) with an orientation tilted relative to the plane of the membrane leaflet (Barrett et al., 2012, Monk et al., 2014, Vostrikov et al., 2010). Their mutation could affect receptor activation by releasing constraints on the helical tilt angle and promote new TMD orientations. Our analysis of the R678Q HER2 mutation at the TMD/JMD interface suggests that this mutation indeed stabilizes the native TMD dimer in an alternative conformation. A similar mutation of a lysine at the periphery of the bilayer in the constitutively dimeric integrin receptor complexes leads to spontaneous receptor activation, presumably due to the destabilization of the inactive TMD dimers in the membrane (Tohyama et al., 2003). The juxtamembrane region plays a critical role in EGFR activation and is highly conserved in HER2 (Jura et al., 2009, Red Brewer et al., 2009). The constitutively active juxtamembrane latch mutation Q709L is predicted to fit well within a hydrophobic pocket in the activator kinase thereby enhancing the receiver-activator interaction. A similar set of mutations introducing hydrophobic residues in the juxtamembrane latch to optimize binding to other small hydrophobic pockets along the juxtamembrane latch-binding groove on the C-lobe of the activator kinase have been identified as cancer mutations in EGFR and HER3 (Littlefield et al., 2014, Red Brewer et al., 2009). Hence, the Q709L mutation seems to utilize a similar strategy to drive constitutive HER2 receptor signaling in cancer. Besides amplification and mutations in the KD and ECD, mutations in the TMD/JMD domains expand the list of actionable HER2 alterations. We found that they occur in multiple cancers. In addition to somatic HER2 mutations, we investigated a CARIPORIDE australia germline HER2 TMD mutation, G660D, that we identified in a family from India, where the individuals carrying the mutation developed lung cancer at an early age. Germline mutations in other oncogenes, such as AKT1 E17K (Lindhurst et al., 2011), EGFR T790M (Bell et al., 2005), PIK3CA G118D (Orloff et al., 2013), BRAF G469E, and KRAS G60R (Niihori et al., 2006), are known to contribute to familial diseases including cancers. The HER2 G660D mutation is a very rare variant and is not found in the normal population. It was previously reported in a Japanese family where individuals developed lung cancer (Yamamoto et al., 2014). A limited number of genetic variants associated with hereditary forms of lung cancer are known and they include a dominantly inherited germline EGFR T790M variant (Bell et al., 2005, Gazdar et al., 2014). Interestingly, the EGFR and HER2 mutant hereditary cancer patients are predominantly never-smokers, including affected individuals studied here (Gazdar et al., 2014). Individuals carrying the HER2 G660D mutation are normal at birth, suggesting the expression of this mutant allele is not developmentally detrimental despite the potential expression of a constitutively active HER2 during development. Similarly, germline expression of the HER2 TMD V659E (neu) mutant cDNA in the presence of endogenous mouse ERBB2 did not affect the development of mice (Andrechek et al., 2004). Unlike human subjects with this mutation who develop lung cancer, the mice were free of cancer for over 24 months (Andrechek et al., 2004). These observations suggest that further studies are needed to establish the secondary events leading to carcinogenesis in HER2 mutant carriers. Our data also highlight important clinical considerations for treating the TMD- and JMD-activating mutations in HER2. Pertuzumab further stimulated signaling by G660D HER2 in BaF3 cells. Pertuzumab is a bivalent antibody and works by blocking ligand-dependent HER2/HER3 heterodimer signaling. However, in the context of G660D HER2-expressing BaF3 cells, it likely promotes HER2 activation by further clustering homodimers stabilized by TMD interactions leading to elevated sustained signaling. In contrast, the germline G660D HER2 patient reported here responded well to afatinib in a fourth line setting. Similarly, patients having lung cancer with somatic HER2 V659E or V659E/G660R mutations showed a durable response to afatinib (Ou et al., 2017). Taken together, our results suggest that HER2 TMD and JMD mutant patients are likely candidates for HER2 targeted therapy in the clinic.