Cell line-specific network models of ER+ breast cancer identify potential PI3Kα inhibitor resistance mechanisms and drug combinations

Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. A promising approach to tackle the cancer drug resistance problem is to build mechanistic mathematical models of the signaling network of cancer cells, and explicitly model the dynamics of information flow through this network under distinct genetic conditions and in response to perturbations. In this work, we used a network-based mathematical model to identify sensitivity factors and drug combinations for the PI3K&alpha inhibitor alpelisib, which was recently approved for ER+ PIK3CA mutant breast cancer. We experimentally validated the model-predicted efficacious combination of alpelisib and BH3 mimetics (e.g. MCL1 inhibitors) in ER+ breast cancer cell lines. We also experimentally validated the reduced sensitivity to alpelisib caused by FOXO3 knockdown, which is a novel potential resistance mechanism. Our experimental results showed cell line-specific sensitivity to the combination of alpelisib and BH3 mimetics, which was driven by the choice of BH3 mimetics. We find that cell lines were sensitive to the addition of either MCL1 inhibitor s63845 alone or in combination with BCL-XL/BCL-2 inhibitor navitoclax, and that the need for the combination of both BH3 mimetics was predicted by the expression of BCL-XL. Based on these results, we developed cell line-specific network models that are able to recapitulate the observed differential response to alpelisib and BH3 mimetics, and also incorporate the most recent knowledge on resistance and response to PI3K&alpha inhibitors. Overall, we present an approach for the development, experimental testing, and refining of mathematical models, which we apply to the context of PI3K&alpha inhibitor drug resistance in breast cancer. Our approach predicted and validated PI3K&alpha inhibitor sensitivity factors (FOXO3 knockdown) and drug combinations (BH3 mimetics), and illustrates that network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance.

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Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2020.580251 ◽

2020 ◽

Vol 11 ◽

Author(s):

Zhen Li ◽

Wei Zou ◽

Ji Zhang ◽

Yunjiao Zhang ◽

Qi Xu ◽

...

Keyword(s):

Breast Cancer ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Cancer Drug ◽

Luminal Breast Cancer ◽

Cancer Drug Resistance ◽

Estrogen Receptor Positive ◽

Underlying Mechanisms ◽

Inhibitor Resistance ◽

New Generation

As a new-generation CDK inhibitor, a CDK4/6 inhibitor combined with endocrine therapy has been successful in the treatment of advanced estrogen receptor–positive (ER+) breast cancer. Although there has been overall progress in the treatment of cancer, drug resistance is an emerging cause for breast cancer–related death. Overcoming CDK4/6 resistance is an urgent problem. Overactivation of the cyclin-CDK-Rb axis related to uncontrolled cell proliferation is the main cause of CDK4/6 inhibitor resistance; however, the underlying mechanisms need to be clarified further. We review various resistance mechanisms of CDK4/6 inhibitors in luminal breast cancer. The cell signaling pathways involved in therapy resistance are divided into two groups: upstream response mechanisms and downstream bypass mechanisms. Finally, we discuss possible strategies to overcome CDK4/6 inhibitor resistance and identify novel resistance targets for future clinical application.

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YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development

International Journal of Molecular Sciences ◽

10.3390/ijms222312809 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12809

Author(s):

Miwa Fujihara ◽

Tadahiko Shien ◽

Kazuhiko Shien ◽

Ken Suzawa ◽

Tatsuaki Takeda ◽

...

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Resistance Mechanisms ◽

Resistant Cell ◽

Resistant Cell Line ◽

Trastuzumab Emtansine ◽

Her2 Positive

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

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