Afatinib combined with anlotinib in the treatment of lung adenocarcinoma patient with novel HER2 mutation: a case report and review of the literature

Background HER2 is a member of the ERBB family of receptor tyrosine kinases, and HER2 mutations occur in 1–4% of non-small cell lung cancer (NSCLC) as an oncogenic driver mutation. We found a rare mutation of HER2 p.Asp769Tyr in NSCLC. Case presentation We presented a case of a 68-year-old nonsmoking male patient with brain metastasis from lung adenocarcinoma harboring a rare mutation of HER2 p.Asp769Tyr. After multiple lines of treatment, he obtained a durable response (10 months) to afatinib and anlotinib. Conclusion We reported for the first time that afatinib and anlotinib have successfully treated lung adenocarcinoma with HER2 p.Asp769Tyr mutation. This finding can provide an insight into the optimal treatment of lung adenocarcinoma patients with novel mutations. Additionally, we summarized the efficacy of targeted therapy for HER2 mutant lung cancer in this article.

AKAP13 couples GPCR signaling to mTORC1 inhibition

The mammalian target of rapamycin complex 1 (mTORC1) senses multiple stimuli to regulate anabolic and catabolic processes. mTORC1 is typically hyperactivated in multiple human diseases such as cancer and type 2 diabetes. Extensive research has focused on signaling pathways that can activate mTORC1 such as growth factors and amino acids. However, less is known about signaling cues that can directly inhibit mTORC1 activity. Here, we identify A-kinase anchoring protein 13 (AKAP13) as an mTORC1 binding protein, and a crucial regulator of mTORC1 inhibition by G-protein coupled receptor (GPCR) signaling. GPCRs paired to Gαs proteins increase cyclic adenosine 3’5’ monophosphate (cAMP) to activate protein kinase A (PKA). Mechanistically, AKAP13 acts as a scaffold for PKA and mTORC1, where PKA inhibits mTORC1 through the phosphorylation of Raptor on Ser 791. Importantly, AKAP13 mediates mTORC1-induced cell proliferation, cell size, and colony formation. AKAP13 expression correlates with mTORC1 activation and overall lung adenocarcinoma patient survival, as well as lung cancer tumor growth in vivo. Our study identifies AKAP13 as an important player in mTORC1 inhibition by GPCRs, and targeting this pathway may be beneficial for human diseases with hyperactivated mTORC1.

Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib

ROS1 rearrangement, identified in ~2% of non-small cell lung cancer (NSCLC), has defined a distinctive molecular subtype. Patients with ROS1 fusion have been shown to be highly sensitive to treatment with crizotinib. However, the efficacy of crizotinib in NSCLC patients with double ROS1 fusions remains to be elucidated. Here, we report a 40-year-old male diagnosed with stage IIIA lung adenocarcinoma. Two ROS1 fusions [SDC4-ROS1 (EX2:EX32) and ROS1-GK (EX31:EX13)] were detected simultaneously in tumor tissue of this patient by next-generation sequencing. Crizotinib was administered, and the patient showed a partial response in lung lesions. Nevertheless, a brain lesion was found at 8 months after treatment. The slightly short duration of response may be related to the presence of ROS1-GK rearrangement. This case proved that patients with SDC4-ROS1 and ROS1-GK fusions may be sensitive to crizotinib, but short progression-free survival of this case showed that the presence of ROS1-GK rearrangement may affect the efficacy of crizotinib. A large-scale investigation on the efficacy of ROS1 inhibitors in patients with complex ROS1 fusions should be conducted in the future.

BRAF p.V600E Mutation as Acquired Resistance Mechanism of Lorlatinib in a ROS1 Rearrangement Lung Adenocarcinoma Patient with Primary Ceritinib Resistance

Both crizotinib and ceritinib are recommended as first-line theray for NSCLC with ROS1 rearrangements, with the latter having stronger infiltration ability across blood-brain barrier. Here we report for the first time that a brain metastatic adenocarcinoma patient with CD74-ROS1 rearrangement was sensitive to crizotinib but resistant to ceritinib. Intracranial progression happened after 7 months of crizotinib, and sencond-line lorlatinib resulted in partial response and a PFS of 8 months. Upon lorlatinib resistance, repeated NGS detection of ctDNA from peripheral blood showed BRAF p.V600E, CD74-ROS1 and ROS1 pG2032R. Then, Trametinib, dabrafenib, and cabozantinib was administered to the patient. However, disease progressed very quickly and the patient passed away only one month later, with a overall survival of months. The last ctDNA test, one week before death of the patient, found that BRAF p.V600E disappeared, leaving only CD74-ROS1and ROS1 pG2032R,with a very high frequency. To our knowledge, this is the first case report of a ROS-1 rearrangement lung cancer patient that is sensitive to crizotinib but resistant to ceritinib, and BRAF p.V600E as resistant mechanism for lorlatinib.

Case Report: Identification of Two Rare Fusions, PDK1-ALK and STRN-ALK, That Coexist in a Lung Adenocarcinoma Patient and the Response to Alectinib

Several double ALK fusions coexisting in one patient have been reported. However, few studies have reported the clinical efficacy of ALK inhibitors in rare double ALK fusions. Here, we described a rare PDK1-ALK, STRN-ALK double-fusion variant in a patient with metastatic lung adenocarcinoma. The patient responded well to alectinib (600 mg) twice daily. This case shows a promising treatment option for patients with rare ALK double-fusion variants.