AKT/mTOR as a targetable hub to overcome multimodal resistance to EGFR inhibitors in oesophageal squamous cell carcinoma

TY - JOUR

T1 - AKT/mTOR as a targetable hub to overcome multimodal resistance to EGFR inhibitors in oesophageal squamous cell carcinoma

AU - Spender, Lindsay C.

AU - Watt, Dale M.

AU - Baxter, Mark A.

AU - Shuttleworth, Morven K.

AU - Walker, Kateah

AU - Savage, Alice R.

AU - Clements, Hollie A.

AU - Kapelyukh, Yury

AU - Bray, Susan E.

AU - King, Sharon I.

AU - Wolf, C. Roland

AU - Inman, Gareth J.

AU - Walsh, Shaun V.

AU - Blyth, Karen

AU - Petty, Russell D.

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/9/21

Y1 - 2025/9/21

N2 - Background: Oesophageal squamous cell carcinoma (ESCC) is associated with late-stage diagnosis, limited treatment options, the development of drug resistance and poor outcome. Epidermal growth factor receptor is frequently dysregulated in ESCC. EGFR copy number gain and/or protein overexpression are beneficial as predictive biomarkers for EGFR inhibitor therapy; however, inherent and acquired resistance limit response rates, and durable disease control is infrequent. Methods: This study investigates the causes of resistance to the off-patent EGFR inhibitor gefitinib in three gefitinib-resistance model systems: intrinsic, acquired resistance and growth factor (TGFβ)-induced resistance. Findings from studies in 13 ESCC cell lines were validated in tumour specimens from the GO2 clinical trial (n = 32), publicly available ESCC datasets (n = 264), cell line-derived xenograft (CDX) and patient-derived organoid (PDO) model systems. Results: Gefitinib resistance in ESCC was associated with diverse mechanisms, including RTK signalling via PDGFRβ and IGFBP3/IGF1/IGF1R, as well as EMT, but was consistently associated with the maintenance of signalling via AKT across multiple cell lines and model systems. AKT or mTOR inhibitors synergised with gefitinib in 2D and anchorage-independent 3D assays. Gefitinib plus the AKT inhibitor capivasertib (Truqap™) was efficacious in human CDX and PDO models. Discussion: Combining AKT/mTOR inhibitors with EGFR inhibitors in EGFR-driven ESCC shows synergism but with elevated toxicity. Monotherapy AKT/mTOR inhibitors or combined therapy at reduced doses could offer improved, cost-effective therapy options for gefitinib-resistant cancer.

AB - Background: Oesophageal squamous cell carcinoma (ESCC) is associated with late-stage diagnosis, limited treatment options, the development of drug resistance and poor outcome. Epidermal growth factor receptor is frequently dysregulated in ESCC. EGFR copy number gain and/or protein overexpression are beneficial as predictive biomarkers for EGFR inhibitor therapy; however, inherent and acquired resistance limit response rates, and durable disease control is infrequent. Methods: This study investigates the causes of resistance to the off-patent EGFR inhibitor gefitinib in three gefitinib-resistance model systems: intrinsic, acquired resistance and growth factor (TGFβ)-induced resistance. Findings from studies in 13 ESCC cell lines were validated in tumour specimens from the GO2 clinical trial (n = 32), publicly available ESCC datasets (n = 264), cell line-derived xenograft (CDX) and patient-derived organoid (PDO) model systems. Results: Gefitinib resistance in ESCC was associated with diverse mechanisms, including RTK signalling via PDGFRβ and IGFBP3/IGF1/IGF1R, as well as EMT, but was consistently associated with the maintenance of signalling via AKT across multiple cell lines and model systems. AKT or mTOR inhibitors synergised with gefitinib in 2D and anchorage-independent 3D assays. Gefitinib plus the AKT inhibitor capivasertib (Truqap™) was efficacious in human CDX and PDO models. Discussion: Combining AKT/mTOR inhibitors with EGFR inhibitors in EGFR-driven ESCC shows synergism but with elevated toxicity. Monotherapy AKT/mTOR inhibitors or combined therapy at reduced doses could offer improved, cost-effective therapy options for gefitinib-resistant cancer.

UR - https://www.scopus.com/pages/publications/105009626187

U2 - 10.1038/s41416-025-03093-3

DO - 10.1038/s41416-025-03093-3

M3 - Article

C2 - 40615716

SN - 0007-0920

VL - 133

SP - 709

EP - 722

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 5

ER -