PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer
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PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer. / Talwelkar, Sarang S.; Mayranpaa, Mikko I.; Schuler, Julia; Linnavirta, Nora; Hemmes, Annabrita; Adinolfi, Simone; Kankainen, Matti; Sommergruber, Wolfgang; Levonen, Anna-Liisa; Rasanen, Jari; Knuuttila, Aija; Verschuren, Emmy W.; Wennerberg, Krister.
I: Molecular Oncology, Bind 17, Nr. 5, 2023, s. 747-764.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer
AU - Talwelkar, Sarang S.
AU - Mayranpaa, Mikko I.
AU - Schuler, Julia
AU - Linnavirta, Nora
AU - Hemmes, Annabrita
AU - Adinolfi, Simone
AU - Kankainen, Matti
AU - Sommergruber, Wolfgang
AU - Levonen, Anna-Liisa
AU - Rasanen, Jari
AU - Knuuttila, Aija
AU - Verschuren, Emmy W.
AU - Wennerberg, Krister
PY - 2023
Y1 - 2023
N2 - Treatment with anaplastic lymphoma kinase (ALK) inhibitors significantly improves outcome for non-small-cell lung cancer (NSCLC) patients with ALK-rearranged tumors. However, clinical resistance typically develops over time and, in the majority of cases, resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen and deployed functional drug screens to identify modulators of ALK-inhibitor response. This identified a role for PI3K beta and EGFR inhibition in sensitizing the response regulating resistance to ALK inhibition. Inhibition of ALK elicited activation of EGFR, and subsequent MAPK and PI3K-AKT pathway reactivation. Sensitivity to ALK targeting was enhanced by inhibition or knockdown of PI3K beta. In ALK-rearranged primary cultures, the combined inhibition of ALK and PI3K beta prevented the EGFR-mediated ALK-inhibitor resistance, and selectively targeted the cancer cells. The combinatorial effect was seen also in the background of TP53 mutations and in epithelial-to-mesenchymal transformed cells. In conclusion, combinatorial ALK- and PI3K beta-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.
AB - Treatment with anaplastic lymphoma kinase (ALK) inhibitors significantly improves outcome for non-small-cell lung cancer (NSCLC) patients with ALK-rearranged tumors. However, clinical resistance typically develops over time and, in the majority of cases, resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen and deployed functional drug screens to identify modulators of ALK-inhibitor response. This identified a role for PI3K beta and EGFR inhibition in sensitizing the response regulating resistance to ALK inhibition. Inhibition of ALK elicited activation of EGFR, and subsequent MAPK and PI3K-AKT pathway reactivation. Sensitivity to ALK targeting was enhanced by inhibition or knockdown of PI3K beta. In ALK-rearranged primary cultures, the combined inhibition of ALK and PI3K beta prevented the EGFR-mediated ALK-inhibitor resistance, and selectively targeted the cancer cells. The combinatorial effect was seen also in the background of TP53 mutations and in epithelial-to-mesenchymal transformed cells. In conclusion, combinatorial ALK- and PI3K beta-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.
KW - ALK-rearranged lung cancer
KW - combination treatment
KW - drug resistance
KW - EGFR
KW - EML4-ALK
KW - NSCLC
KW - patient-derived cells
KW - PI3K beta
KW - CRIZOTINIB
KW - RESISTANCE
KW - P110-BETA
KW - COMBINATION
KW - MUTATION
KW - AZD8186
KW - BREAST
KW - GROWTH
KW - GENE
U2 - 10.1002/1878-0261.13342
DO - 10.1002/1878-0261.13342
M3 - Journal article
C2 - 36423211
VL - 17
SP - 747
EP - 764
JO - Molecular Oncology
JF - Molecular Oncology
SN - 1574-7891
IS - 5
ER -
ID: 339129425