ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer

Abstract

Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment—Progresses in Their Use in Combined Cancer Therapy

“…LUR has been evaluated in combination with ICIs (anti-PD-L1 and anti-CTLA-4 [ 152 ]) and in combination with irinotecan [ 153 , 154 ], ATR [ 122 , 155 ] alone or combined with ATM [ 156 ] and PARP [ 157 ] inhibitors, anti-VEGF [ 158 ] combined with cisplatin [ 83 , 159 , 160 ], paclitaxel [ 158 ], gemcitabine [ 161 ], capecitabine [ 162 ], doxorubicin [ 41 , 163 , 164 ], and immunomodulatory biomolecules such as antibody-drug complexes commonly referred to as ADCs (4C9-DM1 that targets c-Kit [ 165 ]).…”

“…For LUR in combination with ICIs: anti-PD-L1 and anti-CTLA-4 showed strong anti-neoplastic effects in osteosarcoma and fibrosarcoma cell lines, and breast cancer and fibrosarcoma murine models [ 152 ]. LUR + berzosertib (ATR inhibitor) showed synergy in SCLC in vivo, organoid, and in vitro models [ 155 ]. LUR + cisplatin showed promising activity in malignant pleural mesothelioma [ 160 ] but it was not feasible in advanced solid tumours due to toxicity issues [ 83 ].…”

“…Redirects T-lymphocyte cytotoxicity to AXL-expressing cells Osteosarcoma [150] TRB + L19-mTNF Pro-inflammatory cytokine Fibrosarcoma [133] Physical agents TRB + radiotherapy Lung cancer, colon cancer [138] Advanced soft tissue sarcoma [139] Localized resectable myxoid liposarcoma [140,141] Retroperitoneal leiomyosarcoma [151] TRB + hyperthermia Osteosarcoma, liposarcoma, synovial sarcoma [137] LUR has been evaluated in combination with ICIs (anti-PD-L1 and anti-CTLA-4 [152]) and in combination with irinotecan [153,154], ATR [122,155] alone or combined with ATM [156] and PARP [157] inhibitors, anti-VEGF [158] combined with cisplatin [83,159,160], paclitaxel [158], gemcitabine [161], capecitabine [162], doxorubicin [41,163,164], and immunomodulatory biomolecules such as antibody-drug complexes commonly referred to as ADCs (4C9-DM1 that targets c-Kit [165]).…”

P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation

“…Recently, it was preclinically observed that the RNA Pol-II inhibitor lurbinectedin, which induces DNA damage, exhibited strong synergy with the ATR inhibitor berzosertib in SCLC cell lines. Synergy was reduced with high p21 expression, as p21 causes G1 arrest [ 66 ]. It could be possible that SCLC cells with p53 aberrations, and thus reduced levels of the protein p21, would respond better to the combination of berzosertib and lurbinectedin.…”

Actionable Driver Events in Small Cell Lung Cancer

“…In combination with topotecan, it has a cytotoxic effect and activates the STING (STimulator of INterferon Genes) pathway, implying that ATR-TOP1 inhibition may improve response to immune checkpoint therapy in STING-low SCLC tumors [ 80 ]. In addition, synergy of M6620 with lurbinectedin has been demonstrated in multiple SCLC cell lines, organoids, and in vivo models [ 81 ], and their combined effectiveness is currently being assessed in a clinical trial (NCT04802174). Finally, other M6620 combinations are under investigation in SCLC, such as a combination with the Trop2 inhibitor molecule sacituzumab-govitecan (NCT04826341), a transmembrane glycoprotein that has emerged as a promising molecular target for lung cancer treatment [ 82 ].…”