Details

Autor(en) / Beteiligte

• Kitajima, Shunsuke
• Tani, Tetsuo
• Springer, Benjamin F.
• Campisi, Marco
• Osaki, Tatsuya
• Haratani, Koji
• Chen, Minyue
• Knelson, Erik H.
• Mahadevan, Navin R.
• Ritter, Jessica
• Yoshida, Ryohei
• Köhler, Jens
• Ogino, Atsuko
• Nozawa, Ryu-Suke
• Sundararaman, Shriram K.
• Thai, Tran C.
• Homme, Mizuki
• Piel, Brandon
• Kivlehan, Sophie
• Obua, Bonje N.
• Purcell, Connor
• Yajima, Mamiko
• Barbie, Thanh U.
• Lizotte, Patrick H.
• Jänne, Pasi A.
• Paweletz, Cloud P.
• Gokhale, Prafulla C.
• Barbie, David A.

Titel

MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer

Ist Teil von

• Cancer cell, 2022-10, Vol.40 (10), p.1128-1144.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2′3′-cyclic GMP-AMP (2′3′-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity. [Display omitted] •KL mutant cells are sensitive to intracellular 2′-3′cGAMP accumulation•MPS1i potently generates 2′-3′-cGAMP via cGAS sensing of micronuclei•De-repression of STING further co-opts this vulnerability and recruits T/NK cells•Sequential DNMT-MPS1 inhibitor treatment effectively restores immunogenicity in vivo KRAS-LKB1 (KL) lung cancers epigenetically silence STING and resist PD-1 blockade. Here, Kitajima et al. discover that MPS1 inhibition strongly reactivates KL cGAS-STING signaling following epigenetic STING de-repression. Microfluidic and animal models demonstrate potent T/NK cell recruitment by this combination, reversing anti-PD-1 resistance and revealing a strategy translatable to the clinic.