Reference Detail

Ref Type

Journal Article

PMID

(37748191)

Authors

Chen N, Tyler LC, Le AT, Welsh EA, Fang B, Elliott A, Davies KD, Danhorn T, Riely GJ, Ladanyi M, Haura EB, Doebele RC

Title

MIG6 Mediates Adaptive and Acquired Resistance to ALK/ROS1 Fusion Kinase Inhibition through EGFR Bypass Signaling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	23	1	2024 Jan 03	92-105	Mol Cancer Ther

URL

Abstract Text

Despite the initial benefit from tyrosine kinase inhibitors (TKI) targeting oncogenic ALK and ROS1 gene fusions in non-small cell lung cancer, complete responses are rare and resistance ultimately emerges from residual tumor cells. Although several acquired resistance mechanisms have been reported at the time of disease progression, adaptative resistance mechanisms that contribute to residual diseases before the outgrowth of tumor cells with acquired resistance are less clear. For the patients who have progressed after TKI treatments, but do not demonstrate ALK/ROS1 kinase mutations, there is a lack of biomarkers to guide effective treatments. Herein, we found that phosphorylation of MIG6, encoded by the ERRFI1 gene, was downregulated by ALK/ROS1 inhibitors as were mRNA levels, thus potentiating EGFR activity to support cell survival as an adaptive resistance mechanism. MIG6 downregulation was sustained following chronic exposure to ALK/ROS1 inhibitors to support the establishment of acquired resistance. A higher ratio of EGFR to MIG6 expression was found in ALK TKI-treated and ALK TKI-resistant tumors and correlated with the poor responsiveness to ALK/ROS1 inhibition in patient-derived cell lines. Furthermore, we identified and validated a MIG6 EGFR-binding domain truncation mutation in mediating resistance to ROS1 inhibitors but sensitivity to EGFR inhibitors. A MIG6 deletion was also found in a patient after progressing to ROS1 inhibition. Collectively, this study identifies MIG6 as a novel regulator for EGFR-mediated adaptive and acquired resistance to ALK/ROS1 inhibitors and suggests EGFR to MIG6 ratios and MIG6-damaging alterations as biomarkers to predict responsiveness to ALK/ROS1 and EGFR inhibitors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK	lung non-small cell carcinoma	sensitive	Afatinib + Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Gilotrif (afatinib) and Alecensa (alectinib) increased inhibition of downstream signaling, viability, and residual colony formation in a non-small cell lung cancer cell line harboring EML4-ALK compared to Alecensa (alectinib) treatment alone in culture (PMID: 37748191).	37748191
EML4 - ALK ALK C1156Y ALK I1171T ALK L1198F	lung non-small cell carcinoma	sensitive	Afatinib + Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Gilotrif (afatinib) and Xalkori (crizotinib) further inhibited viability of a patient-derived non-small cell lung cancer cell line harboring EML4-ALK (e6:e19) with ALK C1156Y, I1171T, and L1198F compared to Xalkori (crizotinib) alone in culture (PMID: 37748191).	37748191
EML4 - ALK	lung non-small cell carcinoma	sensitive	Afatinib + Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Gilotrif (afatinib) and Xalkori (crizotinib) increased inhibition of downstream signaling, viability, and residual colony formation in a non-small cell lung cancer cell line harboring EML4-ALK compared to Xalkori (crizotinib) treatment alone in culture (PMID: 37748191).	37748191
EML4 - ALK ALK C1156Y ALK I1171T ALK L1198F	lung non-small cell carcinoma	sensitive	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) inhibited viability of a patient-derived non-small cell lung cancer cell line harboring EML4-ALK (e6:e19) with ALK C1156Y, I1171T, and L1198F in culture (PMID: 37748191).	37748191
EML4 - ALK ALK C1156Y	lung non-small cell carcinoma	sensitive	Afatinib + Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Gilotrif (afatinib) and Lorbrena (lorlatinib) further inhibited viability of a patient-derived non-small cell lung cancer cell line harboring EML4-ALK (e6:e19) with ALK C1156Y compared to Lorbrena (lorlatinib) alone in culture (PMID: 37748191).	37748191
EML4 - ALK ALK L1196M ALK D1203N	lung non-small cell carcinoma	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK (e13:e20) with ALK L1196M and D1203N was resistant to Xalkori (crizotinib) in culture (PMID: 37748191).	37748191
EML4 - ALK ALK C1156Y ALK I1171T ALK L1198F	lung non-small cell carcinoma	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK (e6:e19) with ALK C1156Y, I1171T, and L1198F was resistant to Lorbrena (lorlatinib) in culture (PMID: 37748191).	37748191