CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR -mutant non-small cell lung cancer.

Background: Epidermal growth factor receptor ( EGFR ) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR -mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR -mutant NSCLC before the emergence of acquired resistance.
Methods: Using several EGFR -mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR -mutant NSCLC.
Results: In several EGFR -mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR -mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation.
Conclusions: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR -mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR -mutant NSCLC.
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-99/coif). EI received honoraria from AstraZeneca K.K., Takeda Pharmaceutical Company Limited, Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., Novartis Pharma K.K., ONO PHARMACEUTICAL CO., LTD., Merck & Co., Inc., Bristol-Myers Squibb Company, Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., and Nippon Kayaku Co., Ltd. EI received additional research funding from Takeda Pharmaceutical Company Limited, Pfizer Japan Inc., AstraZeneca K.K., MSD, Janssen Pharmaceutical K.K., and Nippon Kayaku Co., Ltd. HK received honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, MSD, and Bristol-Myers Squibb. NA received honoraria from Novartis Pharma, Kyowa Kirin, AbbVie, Chugai Pharmaceutical, Meiji Seika Pharma, Otsuka Pharmaceutical, Asahi Kasei Pharma, Nippon Shinyaku, Astellas Pharma, Sanofi. NA received additional research funding from Novartis Pharma. KN received honoraria from AstraZeneca, Boehringer Ingelheim, Kyowa Kirin, Eli Lilly Japan, Chugai Pharmaceutical, Nippon Kayaku, TAIHO Pharmaceutical, MSD, Ono Pharmaceutical, Takeda Pharmaceutical, Pfizer Japan, Bristol-Myers Squibb, Pfizer, Elekta, Janssen Pharmaceutical, and Daiichi Sankyo. GM received honoraria from Chugai Pharmaceutical Co., Ltd., Norartis International AG, Kyowa Kirin Co., Ltd., Merck & Co., Inc., and ONO PHARMACEUTIAL CO., LTD. TK received honoraria from Bristol-Myers Squibb, Taiho Pharmaceutical, Kyowa Hakko Kirin, AstraZeneca, Ono Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, MSD, Pfizer Japan, Eli Lilly Japan, Novartis International, Boehringer Ingelheim, and Towa Pharmaceutical. KO received honoraria from Lilly, Nihon kayaku, Kyowa-Kirin, Boehringer Ingelheim, Novartis, and Chugai pharmaceutical; research funding from Boehringer Ingelheim, Novartis, AstraZeneca, Eli Lilly, MSD, Chugai pharmaceutical, and Daiichi-Sankyo outside the submitted work. KO received research drugs from Ono pharma, or, Novartis, Genentech under MTA outside the submitted work. KH received honoraria from Pfizer Japan, AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Nippon Kayaku, and Boehringer-Ingelheim. KH received additional research funding from MSD, AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Bristol-Myers Squibb, and AbbVie. MT received honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Pfizer Japan, Novartis Pharma, TAIHO Pharmaceutical, and Bristol-Myers Squibb. YM received honoraria form AstraZeneca, Astellas Pharma, Amgen, AbbVie, Eisai, Otsuka Pharmaceutical, Ono Pharmaceutical, KYORIN Pharmaceutical, Kyowa Kirin, Sanofi, Celgene, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, TERUMO, Chugai Pharmaceutical, Nippon Shinyaku, Novartis Pharma, Pfizer Japan, Mundipharma, Human Life CORD Japan, Meiji Seika Pharma, Janssen Pharmaceutical, Yakult Honsha, Asahi Kasei Pharma, Viatris, KISSEI PHARMACEUTICAL, and KONICA MINOLTA. YM received additional research funding from Astellas Pharma, Chugai Pharmaceutical, Nippon Shinyaku, AstraZeneca, Novartis Pharma, Janssen Pharmaceutical, and Mundipharma. YM received scholarship donation from Astellas Pharma, Asahi Kasei Pharma, Eisai, Otsuka Pharmaceutical, Kyowa Kirin, TAIHO Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Japan Blood Products Organization, Nippon Shinyaku, Mallinckrodt Pharma, REGiMMUNE, and AstraZeneca. KK received honoraria from AstraZeneca, Eli Lilly Japan, TAIHO Pharmaceutical, Chugai Pharmaceutical, Pfizer Japan, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Merck Biopharma, Nippon Kayaku, and Takeda Pharmaceutical. KK received consulting fee from Nippon Kayaku and NIPRO. KK received additional research funding from Boehringer Ingelheim, Ono Pharmaceutical, Novartis International, and Takeda Pharmaceutical. KK received scholarship donation from KYORIN Pharmaceutical, SHIONOGI, Nippon Kayaku, Taiho Pharmaceutical, and Chugai Pharmaceutical. The other authors have no conflicts of interest to declare.
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