Dr Machaalani on the Incidence of ERBB2 Amplifications Across Race, Sex, and Cancer Type

Marc Machaalani, MD, research fellow, Department of Medicine, Dana-Farber Cancer Institute, discusses an investigation into the distribution of 

 (HER2) amplifications across sex, race, and cancer type in patients with cancer. Notably, findings from this analysis were presented at the 

In April 2024, fam-trastuzumab deruxtecan-nxki (Enhertu) 

received accelerated approval from the FDA

 for the treatment of patients with pretreated, metastatic or unresectable HER2-positive tumors. Machaalani and colleagues investigated the distribution of 

 amplifications, often linked to HER2 overexpression, across various subgroups of patients with cancer based on race, sex, and cancer type. Investigators analyzed data from 103,786 patients within the Genomics Evidence Neoplasia Information Exchange (GENIE) registry and identified 

 amplifications in 4.02% of samples (n = 5040), with the highest rates observed in esophageal adenocarcinoma (19.4%), breast cancer (12%), salivary gland cancer (7.2%), bladder cancer (6.1%), and endometrial cancer (4.7%), he explains.

Significant differences emerged across subgroups, he continues. For example, male patients with esophagogastric cancer exhibited higher rates of 

 amplifications compared with female patients with these diseases, at 14.8% vs 9.5%, respectively. Conversely, female patients with breast cancer had higher rates of 

 amplifications than their male counterparts, Machaalani reports. Racial disparities were also observed, with Asian patients with colorectal and bladder cancers showing higher rates of 

 amplifications than White and Black patients with these diseases. Furthermore, Black patients with endometrial cancer displayed higher rates of these amplifications vs White patients with this disease, he expresses.

 amplifications were more frequently detected in metastatic tumors compared with primary tumors, with notable findings in vaginal cancers, Machaalani continues. These results emphasize the importance of understanding the heterogeneity in HER2 amplification across subgroups, as it has significant implications for the personalized use of HER2-targeted therapies, he states. By acknowledging these differences, oncologists can better tailor treatment approaches, improving outcomes in patients with HER2-positive tumors, according to Machaalani. Furthermore, these insights are valuable for guiding clinical trial designs, ensuring they account for the variability in HER2 amplification across different demographics and tumor types, Machaalani says. This study underscores the need for personalized therapeutic strategies to optimize care for diverse patient populations, he concludes.

Videos

Marc Machaalani, MD, discusses an investigation into the distribution of ERBB2 amplifications across sex, race, and varying cancer types.

Dr Machaalani on the Interaction Between c-Met and AXL in RCC

Marc Machaalani, MD, research fellow, Department of Medicine, Dana-Farber Cancer Institute, discusses the rationale for examining AXL and its interaction with c-Met, as well as how inhibition of these targets may impact c-Met inhibitors in renal cell carcinoma (RCC).

Notably, Machaalani and colleagues conducted a study that was presented at the 

. c-Met is a receptor tyrosine kinase that is notably overexpressed in kidney cancer, playing a crucial role in the disease’s progression, he begins. Cabozantinib (Cabometyx) is a TKI that, although effective against c-Met, also functions as a nonspecific inhibitor because it simultaneously targets AXL and its ligand, Machaalani explains. This is particularly important since the presence of both AXL and Gas6 have been associated with poor prognosis in patients with kidney cancer, indicating that their inhibition could be beneficial in managing the disease, according to Machaalani. Given this, the study set out to investigate the intricate relationship between AXL and c-Met and to explore whether inhibiting or silencing AXL could influence, prevent, or even overcome the acquired resistance to cabozantinib and other c-Met inhibitors in RCC, he reports.

To delve into this, investigators generated cabozantinib-resistant cells from wild-type cabozantinib-sensitive cells. These resistant cells provided a model to study the mechanisms underlying resistance to cabozantinib and potentially other c-Met inhibitors, he continues. Investigators usedchromatin immunoprecipitation sequencing to perform H3K27 acetylation, a specific post-translational histone modification that is associated with active enhancers and promoters.

In parallel, investigators performed RNA sequencing to investigate the differentially expressed genes between the cabozantinib-sensitive and -resistant cell lines. By analyzing these gene expression profiles, they aimed to uncover the pathways that were either upregulated or downregulated in response to cabozantinib resistance, he adds. To test this hypothesis, investigators used TP-0903, a small molecule inhibitor specifically targeting AXL, to determine whether inhibiting AXL could reverse or mitigate cabozantinib resistance in these resistant cells, Machaalani concludes.

Marc Machaalani, MD, discusses the rationale for examining AXL and its interaction with c-Met in renal cell carcinoma.

Overcoming Acquired Resistance Through AXL and c-Met Inhibition in RCC

Dr Machaalani on Overcoming Acquired Resistance Through AXL and c-Met Inhibition in RCC

Marc Machaalani, MD, research fellow, Department of Medicine, Dana-Farber Cancer Institute, discusses the pro-tumorigenic role of AXL through its interaction with c-Met and how inhibition of these targets may prevent acquired resistance to c-Met inhibitors in renal cell carcinoma (RCC).

Machaalani and colleagues conducted a study to evaluate the crosstalk between AXL and c-Met and explore the potential of targeting AXL to prevent resistance to c-Met inhibition. In this study, a cabozantinib (Cabometyx)-resistant cell line was generated from wild-type cabozantinib-sensitive Caki-1 clear cell RCC (ccRCC) cells, and CRISPR/Cas9-mediated AXL knockout cells were produced from 786-O ccRCC cells.

revealed that cells resistant to cabozantinib and c-MET inhibitors exhibit distinct transcriptomic and epigenomic profiles, Machaalani reports. Findings showed differentially marked H3K27ac regions and up- or downregulated genes and pathways in cabozantinib-resistant cells compared with cabozantinib-sensitive cells. RNA sequencing also showed that epithelial-mesenchymal transition, hypoxia, and KRAS signaling pathways were significantly downregulated in AXL knockout cells compared with control 786-O cells. These findings indicate that cells repeatedly exposed to c-Met inhibition undergo epigenetic rewiring, leading to downstream transcriptomic and phenotypical changes, such as resistance, Machaalani states.

Collaborating with Boston Children’s Hospital, the research team found that AXL and c-Met are overexpressed and form a complex in kidney cancer cells compared with primary renal proximal tubule epithelial cells, he continues. Upon c-Met inhibition, novel expression of AXL and c-Met was observed, along with increased c-Met and AXL expression in RCC and c-Met phosphorylation in the presence of HGF, Machaalani details.

Moreover, silencing AXL with an AXL-specific small molecule inhibitor, TP-0903, was found to block cabozantinib-mediated increases in c-Met expression and induce apoptosis in cabozantinib-resistant cells, Machaalani says. These findings indicate that targeting AXL alongside c-Met could overcome or even prevent the development of resistance to cabozantinib in patients with RCC, Machaalani concludes.

Marc Machaalani, MD, discusses how inhibition of AXL and c-Met may prevent acquired resistance to c-Met inhibitors in renal cell carcinoma.

Marc Machaalani, MD

Articles

Dr Machaalani on the Incidence of ERBB2 Amplifications Across Race, Sex, and Cancer Type

Dr Machaalani on the Interaction Between c-Met and AXL in RCC

Dr Machaalani on Overcoming Acquired Resistance Through AXL and c-Met Inhibition in RCC