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Additional file 2.

Additional file 1.

Additional file 3: Supplemental Figure S1. Endogenous protein expression levels of HN30 and PCI37A cells. Supplemental Figure S2. AXL mRNA expression in HN30-AXL and PCI37A-AXLC1 and -AXLC2 cells. Suppemental Figure S3. Correlation between AXL and NRG1 mRNA expression levels in TCGA HNC primary tumor samples (A) and CCLE HNC cell lines (B).

Additional file 2: Figure 1. AXL leads to cetuximab resistance and increased HER3 activity. Figure 2. HER3 is necessary for AXL to mediate cetuximab resistance. Figure 3. HER3 overexpression alone is insufficient for cetuximab resistance. Figure 4. Exogenous expression of NRG1 leads to cetuximab resistance. Figure 5. AXL regulates NRG1. Figure 6. AXL regulates NRG1 to lead to cetuximab resistance.

Additional file 1. Supplemental materials and methods.

BackgroundWe report the successful treatment of the patient with osimertinib 80mg/day following disease progression and a discordance in the detection of a mechanism of resistance epithelial growth factor receptor (EGFR) T790M between liquid biopsy and tissue biopsy methods.Case presentationA 57-year-old Hispanic male patient initially diagnosed with an EGFR 19 deletion positive lung adenocarcinoma and clinically responded to initial erlotinib treatment. The patient subsequently progressed on erlotinib 150mg/day and repeat biopsies both tissue and liquid were sent for next-generation sequencing (NGS). A T790M EGFR mutation was detected in the blood sample using a liquid biopsy technique, but the tissue biopsy failed to show a T790M mutation in a newly biopsied tissue sample. He was then successfully treated with osimertinib 80mg/day, has clinically and radiologically responded, and remains on osimertinib treatment after 10months.ConclusionsSecond-line osimertinib treatment, when administered at 80mg/day, is both well tolerated and efficacious in a patient with previously erlotinib treated lung adenocarcinoma and a T790M mutation detected by liquid biopsy.

A Baseline NRG1 level in archival tumor samples by treatment group and indication. B Best percentage change from baseline in the sum of lesion diameters by mutational status and treatment; one additional patient with PIK3CA amplification, and who had non-target lesions only, is not shown. Footnote: ERRB3 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, ESCC esophageal squamous cell carcinoma, NRG1 neuregulin 1, PIK3CA amp PIK3CA amplified, PD progressive disease, PTEN phosphatase and tensin homolog, Q2W once every two weeks, QW once weekly, SCCHN squamous cell carcinoma of the head and neck, SD stable disease, UNK unknown; â Cq normalized gene expression. (PDF 201 kb)

A Baseline NRG1 level in archival tumor samples by treatment group and indication. B Best percentage change from baseline in the sum of lesion diameters by mutational status and treatment; one additional patient with PIK3CA amplification, and who had non-target lesions only, is not shown. Footnote: ERRB3 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, ESCC esophageal squamous cell carcinoma, NRG1 neuregulin 1, PIK3CA amp PIK3CA amplified, PD progressive disease, PTEN phosphatase and tensin homolog, Q2W once every two weeks, QW once weekly, SCCHN squamous cell carcinoma of the head and neck, SD stable disease, UNK unknown; â Cq normalized gene expression. (PDF 201 kb)

Adverse events (all grades [≥10%] and grades 3/4) suspected to be drug-related, by treatment group. Footnote: All reported grade 3/4 treatment-related adverse events were of grade 3 severity. Additional grade 3 treatment-related adverse events not shown above: pneumatosis intestinalis (n = 1) and lipase increased (n = 1) in the 40 mg/kg QW RDE group, and asthenia (n = 1) in the 20 mg/kg QW group. Q2W once every two weeks, QW once weekly, RDE recommended dose for expansion. (DOCX 17 kb)

Additional file 1 Fig. S1. Differentially expressed gene in USP22-Ko A549 and H1299 cells. Fig. S2. Impact of knockdown of USP22 on H2Bub1/methylatiom of H3K4/K79, cancer cell proliferation, and cell cycle progression. Fig. S3. Negative USP22 IHC stains in adjacent normal cells and tissues. Figure 4. Impact of knockout of USP22 on in vitro migration and invasion of A549 and H1299 cells. Fig. S5. Elevated USP22 in cancer cells survived cisplatin treatment. Fig. S6. Dynamics of P53 in A549 and USP22-Ko cells after 5 and 10 Gy irradiation.

Summary of criteria for dose-limiting toxicities (CTCAE version 4.03 grading). Footnote: ALT alanine aminotransferase, AST aspartate aminotransferase, CTCAE Common Terminology Criteria for Adverse Events, DLTs dose-limiting toxicities, ULN upper limit of normal. (DOCX 28 kb)

Additional file 1 Fig. S1. Differentially expressed gene in USP22-Ko A549 and H1299 cells. Fig. S2. Impact of knockdown of USP22 on H2Bub1/methylatiom of H3K4/K79, cancer cell proliferation, and cell cycle progression. Fig. S3. Negative USP22 IHC stains in adjacent normal cells and tissues. Figure 4. Impact of knockout of USP22 on in vitro migration and invasion of A549 and H1299 cells. Fig. S5. Elevated USP22 in cancer cells survived cisplatin treatment. Fig. S6. Dynamics of P53 in A549 and USP22-Ko cells after 5 and 10 Gy irradiation.

Adverse events (all grades [â Ľ5%]) requiring dose adjustment/interruption, regardless of causality, by treatment group. Footnote: Q2W once every two weeks, QW once weekly, RDE recommended dose for expansion. (DOCX 15 kb)

Adverse events (all grades [â Ľ5%]) requiring dose adjustment/interruption, regardless of causality, by treatment group. Footnote: Q2W once every two weeks, QW once weekly, RDE recommended dose for expansion. (DOCX 15 kb)

Summary of criteria for dose-limiting toxicities (CTCAE version 4.03 grading). Footnote: ALT alanine aminotransferase, AST aspartate aminotransferase, CTCAE Common Terminology Criteria for Adverse Events, DLTs dose-limiting toxicities, ULN upper limit of normal. (DOCX 28 kb)

Adverse events (all grades [≥10%] and grades 3/4) suspected to be drug-related, by treatment group. Footnote: All reported grade 3/4 treatment-related adverse events were of grade 3 severity. Additional grade 3 treatment-related adverse events not shown above: pneumatosis intestinalis (n = 1) and lipase increased (n = 1) in the 40 mg/kg QW RDE group, and asthenia (n = 1) in the 20 mg/kg QW group. Q2W once every two weeks, QW once weekly, RDE recommended dose for expansion. (DOCX 17 kb)