Primary Resistance to EGFR Tyrosine Kinase Inhibitors: History
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Contributor:
Keigo Kobayashi

The discovery of the efficacy of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients has revolutionized lung cancer therapy. Although almost all responders acquire drug resistance within a few years, many studies have revealed several acquired-resistant mechanisms and developed therapeutic strategies countervailing them, most notably against the EGFR T790M gatekeeper mutation. However, little progress has been made in terms of elucidating the mechanisms of primary resistance. Primary resistance may be defined into two types of resistance, clinically representing patients that do not respond (non-responders) to EGFR-TKIs.

  • EGFR-TKI
  • primary resistance
  • cancer dynamics

1. Introduction

Lung cancer is the most common cause of death due to cancer worldwide [1]. The discovery of epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) as a driver oncogene and the effectiveness of EGFR-tyrosine kinase inhibitors (TKIs) for patients have transformed lung cancer therapy, benefiting 60–70% of these patients [2][3][4][5].
The most prevalent EGFR mutations, accounting for approximately 90%, are deletions in exon 19 and L858R point mutations in exon 21, known as the classical activating mutations [6]. Other, less common EGFR mutations include G719X, S768I, and L861Q, insertions in exon 20, with compound mutations being the most frequent among them [7].
In the context of EGFR-TKI treatment, a significant proportion of responders develop drug resistance within a few years, with median progression-free survival periods extending between 9.2 to 18.9 months for the first through third generations of EGFR-TKIs [1][4][5][8][9][10][11][12]. Numerous investigations have elucidated a variety of acquired-resistance mechanisms, prompting the development of therapeutic countermeasures. Notably, the EGFR T790M mutation has emerged as a predominant resistance mechanism against the first- and second-generation EGFR-TKIs. Consequently, third-generation EGFR-TKIs have been engineered with a heightened specificity for the T790M mutation.

2. Overview of Drug-Induced Cancer Dynamics

A broad and all-encompassing overview of lung cancer dynamics is vital to allow for an understanding of primary resistance mechanisms.
When the drug enters the body, it has a more significant effect on cancer cells than on normal cells, but it can also affect normal cells as a side effect. Lung cancer cells may engage with cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAM), and normal cells, inducing a range of alterations in the tumor microenvironment (TME) (Figure 1).
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Figure 1. Overview of Drug-Induced Cancer Dynamics. The medication can influence tumor cells throughout a seven-tiered pyramidal structure, potentially leading to diverse adaptations in cancer cells in response to the altered conditions induced by the drug.
The drug can infiltrate and affect tumor cells from the top to the bottom of a seven-layer pyramidal hierarchy. Cancer cells adapt and transform in response to the altered conditions brought about by medication exposure. 
A small subset of cancer cells might evade cell death induced by anticancer drugs by transitioning into a reversible state of slow proliferation, referred to as the drug-tolerant persister (DTP) state [13][14][15]. This adaptable state allows cancer cells to withstand drug treatment and may later lead to the development of primary or acquired resistance.
The lower layers of hierarchy represented by genetic alterations or lineage plasticity can show more solid phenotypes. They might be involved in developing “intrinsic primary resistance”. Conversely, at the upper levels of the hierarchy, there are no solid phenotypes of resistance, which might be associated with the emergence of late primary resistance. One reason is that DTP cells can mainly be related to these upper layers [16].

3. Drug-Related Factors

3.1. Pharmacokinetic Mechanisms

The metabolism of each generation of EGFR-TKIs is similar, but distinct. Based on its metabolism by CYP3A enzymes, most EGFR-TKIs, other than afatinib (second-generation), may be affected by CYP enzyme inducers, which might result in false resistance. For instance, dexamethasone, a CYP inducer, led to a 0.6-fold reduction in erlotinib (first-generation) [17]. Other potent CYP inducers like phenytoin and rifampin can lower the level of gefitinib plasma concentrations [18][19]. On the other hand, hepatic enzymes barely metabolize afatinib; hence, CYP-interacting substances are unlikely to have an effect on afatinib PK [20][21].

3.2. Pharmacodynamic Mechanisms

This mechanism is mainly associated with intrinsic primary resistance. For instance, first- and second-generation EGFR-TKIs are ineffective against the EGFR T790M mutation due to the consequent altered conformational structure of EGFR. Thus, patients who had such a mutation originally are non-responders, known as those with intrinsic primary resistance.
Moreover, numerous studies indicate that responses to all-generation EGFR-TKIs vary among EGFR exon 20 mutations due to their heterogeneity [22][23]. A recent study revealed that EGFR mutations, encompassing atypical variations, can be organized into four unique subgroups based on their structures and functions to improve drug sensitivity prediction to targeted therapies: (1) classical-like mutations located away from the ATP-binding pocket; (2) T790M-like mutations within the hydrophobic core; (3) insertions in the loop at the C-terminal end of the αC-helix in exon 20 (Ex20ins-L); and (4) mutations on the inner surface of the ATP-binding pocket or at the C-terminal end of the αC-helix, anticipated to cause compression of P-loop and αC-helix (PACC) [24]. Based on this structural classification, exon 20 mutations are sorted into one of three structural classes ((2), (3), and (4)). Especially among the (3) Ex20ins-L group, patients in the exon 20 far-loop insertions (Ex20ins-FL) subgroup are not sensitive to any targeted drugs, leading to intrinsic primary resistance.

4. Tumor-Related Factors

4.1. Metabolism

4.1.1. DTP Cells and Late Primary Resistance

Cancer cells modify their metabolic processes to adjust to the changes brought about by drug exposure. For example, the Warburg Effect, proposed by Otto Warburg more than 50 years ago, is a phenomenon by which cancer cells harness anaerobic glycolysis to fuel their proliferation rather than mitochondrial oxidative phosphorylation [25]. In contrast, recent research indicates that cancer cells use oxygen via mitochondrial oxidative phosphorylation as much as or more than normal cells [26]. DTP cells, which are exposed by drugs, perform a pivotal role in this situation, leading to late primary resistance for EGFR-TKIs.
Since DTP cells demonstrate a heightened reliance on mitochondrial oxidative phosphorylation, they must regulate the overproduction of oxygen-rich molecules, such as superoxide and lipid peroxide, which arise from the mitochondrial oxidative phosphorylation process. Therefore, DTP cells use glutathione peroxidase 4 (GPX4) to neutralize lipid peroxides. It is confirmed in NSCLC cells that inhibiting GPX4 can lead to an accumulation of lipid peroxides, resulting in ferroptosis, a type of oxidative cell death [27][28].

4.1.2. Lipid Metabolism and Autophagy

Lipid metabolism might also play a role in late primary resistance. Fatty acid β-oxidation is essential for energy generation in mitochondrial oxidative phosphorylation. CD36 acts as the primary transporter for fatty acid absorption. The high methylation of CD36 in lung cancer fills a vital role in cancer progression through fatty acid β-oxidation. As a matter of fact, de-methylation of CD36 can lead to removal of the resistance. Combined treatment with the DNA methylation inhibitor (decitabine) and the histone deacetylase (HDAC) inhibitor (chidamide) effectively curbs lung cancer growth in vivo [29].
Autophagy serves as a cellular survival strategy by breaking down and recycling proteins, macromolecules, and organelles, in contrast to apoptosis, which leads to cell death. It plays a crucial role in clearing out malfunctioning mitochondria generated by reactive oxygen species during mitochondrial respiration. Drug-induced accumulation of these impaired mitochondria can enhance malignancy by amplifying oxidative stress. In a lung cancer mouse model, for example, removing the vital autophagy gene Atg7 has been shown to boost oxidative stress and speed up tumor cell growth [30][31].

4.2. Transcriptome and Epigenome

Epigenetics encompasses gene regulatory processes that do not involve DNA sequences, including DNA methylation, hydroxymethylation, and modifications to histone proteins. The transcriptome is intricately linked to epigenetics. For instance, changes in chromatin structure facilitate the epigenetic control of apoptosis and gene expression. Some long noncoding RNAs are involved in oncogenesis through the regulation of transcription, translation, and epigenetics [32].
A characteristic of DTP cells is their reversible biological ability, which is not determined by the genome, but rather by adaptable epigenomic regulation [13].
Exposure to EGFR-TKIs can boost the expression of the epigenetic modulator KDM5A, which is an H3K4 demethylase. Given that KDM5A inhibits the transcriptional activity of H3K4, its increased expression can contribute to late primary resistance.

4.3. Somatic and Genomic Changes

4.3.1. TP53

p53 can induce cell cycle halting, senescence, and programmed cell death [33]. Alterations in the TP53 gene, which codes for p53, are detected in 35–55% of NSCLC patients and are strongly linked to smoking behaviors [34]. TP53 is the primary concurrent alteration in EGFR-mutant NSCLC patients, occurring in 55–65% of cases [35][36][37].
The TP53 status correlates with reduced effectiveness to EGFR-TKIs. In NSCLC cell lines with wild-type p53, gefitinib can induce apoptosis by upregulating Fas at the plasma membrane and reviving caspase activation, thus increasing TKI responsiveness.

4.3.2. PIK3CA Mutation

PIK3CA is responsible for encoding the active component of PI3K, and its mutations can stimulate the PI3K/AKT pathway [38]. Mutations in PIK3CA are uncommon, occurring in roughly 2–5% of NSCLC cases. The most frequent mutations are E545K in exon 9 and H1047R in exon 20 [39][40][41].
PIK3CA mutations frequently appear alongside other driver mutations, notably EGFR and KRAS [39][42][43]. PI3KCA mutations are present in roughly 3.5% of patients with EGFR mutations and are associated with intrinsic primary resistance to EGFR-TKIs [44][45].

4.3.3. PTEN Alterations

Phosphatase and tensin homologs deleted on chromosome 10 (PTEN) act as tumor suppressors and play a role in various cellular activities, including cell proliferation, survival, growth, metabolism, migration, and apoptosis [46][47][48]. PTEN serves as a primary inhibitor of the PI3K/AKT pathway, and its inactivation is crucial for the onset and progression of lung cancer [49][50]. Loss of PTEN function, found in more than 40% of cases, can activate the PI3K/AKT pathway, accelerating tumor progression and reducing sensitivity to EGFR-TKIs in NSCLC patients [50][51][52]. PTEN mutations occur rarely, in 2–5% of NSCLC cases [53][54].
This is due to PTEN’s role in regulating the endocytic trafficking of EGFR, a crucial mechanism for controlling EGFR signaling [55]. Following the binding of EGF (ligand) to its receptor, EGFR, the receptor-ligand combination is taken up by clathrin-coated vesicles. These vesicles then transport the complex to early endosomes for categorization [56][57]. The EGF/EGFR combination progresses to late endosomes via vesicle maturation and subsequently undergoes lysosomal fusion, leading to receptor degradation [58][59]. PTEN plays a pivotal role in facilitating the transition of ligand-bound EGFR from early endosomes to late endosomes for receptor degradation by regulating the phosphorylation of Rab7 and maturing late endosomes [60].

4.4. Cell of Origin

4.4.1. Lineage Plasticity

Histologic transformation is dominated by small-cell and squamous-cell lung cancer transformation as late primary resistance.
As for the mechanisms of SCLC transformation, there are two hypotheses. One theory is that NSCLC can be histologically differentiated into SCLC by EGFR-TKIs exposure through the inactivation of p53 and RB1 [61]. The other theory is that both SCLC and NSCLC components exist simultaneously in the same tumor. Since EGFR-TKIs can reduce the NSCLC elements of tumors, SCLC elements can remain and become dominant [62].

4.4.2. BIM Deletion Polymorphism

BIM, also referred to as BCL2L11 or B-cell chronic lymphocytic leukemia/lymphoma-like 11, is a proapoptotic member of the Bcl-2 family that solely possesses BH3 domains. These domains of the BIM gene are essential for apoptosis triggered by EGFR-TKIs [63][64][65][66][67]. Since BIM is degraded by ERK signaling, EGFR-TKIs can inhibit the ERK signaling and increase the level of BIM protein, leading to cell apoptosis.
The BIM deletion polymorphism involves a 2903 bp fragment removal in the BIM gene’s intron 2, producing an inactive BIM protein variant. This variant is missing the essential BH3 domain, compromising apoptosis related to EGFR-TKIs and leading to inherent primary resistance to these inhibitors [64]. This BIM deletion polymorphism is found in 12–16% of EGFR-mutant lung cancer patients [68][69], especially in East Asian individuals [64]

5. Tumour Microenvironment (TME)

Exposure to drugs impacts the TME, which is linked to primary resistance against EGFR-TKIs. CAFs, a significant component of the TME, are known to contribute to drug resistance by releasing growth factors and chemokines [70].
Additionally, TAMs and MDSCs play a crucial role in contributing to primary resistance to EGFR-TKIs. Specifically, MDSCs that are positive for S100A9, capable of differentiating into TAMs, have been linked to a diminished response to EGFR-TKIs in NSCLC patients [71]. From a mechanistic perspective, S100A9 enhances ALDH1A1 expression and activates the retinoic acid (RA) signaling pathway, thereby promoting cancer proliferation. Using a pan-RAR antagonist can significantly reduce cancer growth [72].

6. Summary

Removing the primary resistance for EGFR-TKIs has become a topic of increasing interest. Previous studies have focused on individual cancer cells, elucidating the acquired resistance mechanisms and investigating the treatment strategies. However, cancer cells interact with the surrounding environment and find another signal pathway for proliferation as a loophole. Tumors can progress on their own and be assisted by the surrounding environment.

This entry is adapted from the peer-reviewed paper 10.3390/jor3040021

References

  1. Fitzmaurice, C.; Abate, D.; Abbasi, N.; Abbastabar, H.; Abd-Allah, F.; Abdel-Rahman, O.; Abdelalim, A.; Abdoli, A.; Abdollahpour, I.; Abdulle, A.S.M.; et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2019, 5, 1749–1768.
  2. Lynch, T.J.; Bell, D.W.; Sordella, R.; Gurubhagavatula, S.; Okimoto, R.A.; Brannigan, B.W.; Harris, P.L.; Haserlat, S.M.; Supko, J.G.; Haluska, F.G.; et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 2004, 350, 2129–2139.
  3. Paez, J.G.; Jänne, P.A.; Lee, J.C.; Tracy, S.; Greulich, H.; Gabriel, S.; Herman, P.; Kaye, F.J.; Lindeman, N.; Boggon, T.J.; et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004, 304, 1497–1500.
  4. Mok, T.S.; Wu, Y.L.; Thongprasert, S.; Yang, C.H.; Chu, D.T.; Saijo, N.; Sunpaweravong, P.; Han, B.; Margono, B.; Ichinose, Y.; et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 2009, 361, 947–957.
  5. Maemondo, M.; Inoue, A.; Kobayashi, K.; Sugawara, S.; Oizumi, S.; Isobe, H.; Gemma, A.; Harada, M.; Yoshizawa, H.; Kinoshita, I.; et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 2010, 362, 2380–2388.
  6. Rosell, R.; Moran, T.; Queralt, C.; Porta, R.; Cardenal, F.; Camps, C.; Majem, M.; Lopez-Vivanco, G.; Isla, D.; Provencio, M.; et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 2009, 361, 958–967.
  7. Zhang, Y.; Wang, Z.; Hao, X.; Hu, X.; Wang, H.; Wang, Y.; Ying, J. Clinical characteristics and response to tyrosine kinase inhibitors of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations. Chin. J. Cancer Res. 2017, 29, 18–24.
  8. Rosell, R.; Carcereny, E.; Gervais, R.; Vergnenegre, A.; Massuti, B.; Felip, E.; Palmero, R.; Garcia-Gomez, R.; Pallares, C.; Sanchez, J.M.; et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012, 13, 239–246.
  9. Zhou, C.; Wu, Y.L.; Chen, G.; Feng, J.; Liu, X.Q.; Wang, C.; Zhang, S.; Wang, J.; Zhou, S.; Ren, S.; et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011, 12, 735–742.
  10. Park, K.; Tan, E.H.; O’Byrne, K.; Zhang, L.; Boyer, M.; Mok, T.; Hirsh, V.; Yang, J.C.; Lee, K.H.; Lu, S.; et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016, 17, 577–589.
  11. Wu, Y.L.; Cheng, Y.; Zhou, X.; Lee, K.H.; Nakagawa, K.; Niho, S.; Tsuji, F.; Linke, R.; Rosell, R.; Corral, J.; et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol. 2017, 18, 1454–1466.
  12. Soria, J.C.; Ohe, Y.; Vansteenkiste, J.; Reungwetwattana, T.; Chewaskulyong, B.; Lee, K.H.; Dechaphunkul, A.; Imamura, F.; Nogami, N.; Kurata, T.; et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 378, 113–125.
  13. Sharma, S.V.; Lee, D.Y.; Li, B.; Quinlan, M.P.; Takahashi, F.; Maheswaran, S.; McDermott, U.; Azizian, N.; Zou, L.; Fischbach, M.A.; et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010, 141, 69–80.
  14. Hata, A.N.; Niederst, M.J.; Archibald, H.L.; Gomez-Caraballo, M.; Siddiqui, F.M.; Mulvey, H.E.; Maruvka, Y.E.; Ji, F.; Bhang, H.E.; Krishnamurthy Radhakrishna, V.; et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 2016, 22, 262–269.
  15. Raha, D.; Wilson, T.R.; Peng, J.; Peterson, D.; Yue, P.; Evangelista, M.; Wilson, C.; Merchant, M.; Settleman, J. The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation. Cancer Res. 2014, 74, 3579–3590.
  16. Mikubo, M.; Inoue, Y.; Liu, G.; Tsao, M.S. Mechanism of Drug Tolerant Persister Cancer Cells: The Landscape and Clinical Implication for Therapy. J. Thorac. Oncol. 2021, 16, 1798–1809.
  17. Deeken, J.F.; Beumer, J.H.; Anders, N.M.; Wanjiku, T.; Rusnak, M.; Rudek, M.A. Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib. Cancer Chemother. Pharmacol. 2015, 76, 813–819.
  18. Chhun, S.; Verstuyft, C.; Rizzo-Padoin, N.; Simoneau, G.; Becquemont, L.; Peretti, I.; Swaisland, A.; Wortelboer, R.; Bergmann, J.F.; Mouly, S. Gefitinib-phenytoin interaction is not correlated with the C-erythromycin breath test in healthy male volunteers. Br. J. Clin. Pharmacol. 2009, 68, 226–237.
  19. Swaisland, H.C.; Ranson, M.; Smith, R.P.; Leadbetter, J.; Laight, A.; McKillop, D.; Wild, M.J. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin. Pharmacokinet. 2005, 44, 1067–1081.
  20. Shibata, Y.; Chiba, M. The role of extrahepatic metabolism in the pharmacokinetics of the targeted covalent inhibitors afatinib, ibrutinib, and neratinib. Drug Metab. Dispos. 2015, 43, 375–384.
  21. Stopfer, P.; Marzin, K.; Narjes, H.; Gansser, D.; Shahidi, M.; Uttereuther-Fischer, M.; Ebner, T. Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers. Cancer Chemother. Pharmacol. 2012, 69, 1051–1061.
  22. Kosaka, T.; Tanizaki, J.; Paranal, R.M.; Endoh, H.; Lydon, C.; Capelletti, M.; Repellin, C.E.; Choi, J.; Ogino, A.; Calles, A.; et al. Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors. Cancer Res. 2017, 77, 2712–2721.
  23. Robichaux, J.P.; Elamin, Y.Y.; Tan, Z.; Carter, B.W.; Zhang, S.; Liu, S.; Li, S.; Chen, T.; Poteete, A.; Estrada-Bernal, A.; et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat. Med. 2018, 24, 638–646.
  24. Robichaux, J.P.; Le, X.; Vijayan, R.S.K.; Hicks, J.K.; Heeke, S.; Elamin, Y.Y.; Lin, H.Y.; Udagawa, H.; Skoulidis, F.; Tran, H.; et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature 2021, 597, 732–737.
  25. Warburg, O. On the origin of cancer cells. Science 1956, 123, 309–314.
  26. Molina, J.R.; Sun, Y.; Protopopova, M.; Gera, S.; Bandi, M.; Bristow, C.; McAfoos, T.; Morlacchi, P.; Ackroyd, J.; Agip, A.A.; et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat. Med. 2018, 24, 1036–1046.
  27. Hangauer, M.J.; Viswanathan, V.S.; Ryan, M.J.; Bole, D.; Eaton, J.K.; Matov, A.; Galeas, J.; Dhruv, H.D.; Berens, M.E.; Schreiber, S.L.; et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 2017, 551, 247–250.
  28. Viswanathan, V.S.; Ryan, M.J.; Dhruv, H.D.; Gill, S.; Eichhoff, O.M.; Seashore-Ludlow, B.; Kaffenberger, S.D.; Eaton, J.K.; Shimada, K.; Aguirre, A.J.; et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017, 547, 453–457.
  29. Sun, Q.; Zhang, W.; Wang, L.; Guo, F.; Song, D.; Zhang, Q.; Zhang, D.; Fan, Y.; Wang, J. Hypermethylated CD36 gene affected the progression of lung cancer. Gene 2018, 678, 395–406.
  30. Guo, J.Y.; Teng, X.; Laddha, S.V.; Ma, S.; Van Nostrand, S.C.; Yang, Y.; Khor, S.; Chan, C.S.; Rabinowitz, J.D.; White, E. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes Dev. 2016, 30, 1704–1717.
  31. Strohecker, A.M.; Guo, J.Y.; Karsli-Uzunbas, G.; Price, S.M.; Chen, G.J.; Mathew, R.; McMahon, M.; White, E. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov. 2013, 3, 1272–1285.
  32. Ramilowski, J.A.; Yip, C.W.; Agrawal, S.; Chang, J.C.; Ciani, Y.; Kulakovskiy, I.V.; Mendez, M.; Ooi, J.L.C.; Ouyang, J.F.; Parkinson, N.; et al. Functional annotation of human long noncoding RNAs via molecular phenotyping. Genome Res. 2020, 30, 1060–1072.
  33. Zilfou, J.T.; Lowe, S.W. Tumor suppressive functions of p53. Cold Spring Harb. Perspect. Biol. 2009, 1, a001883.
  34. Ma, X.; Le Teuff, G.; Lacas, B.; Tsao, M.S.; Graziano, S.; Pignon, J.P.; Douillard, J.Y.; Le Chevalier, T.; Seymour, L.; Filipits, M.; et al. Prognostic and Predictive Effect of TP53 Mutations in Patients with Non-Small Cell Lung Cancer from Adjuvant Cisplatin-Based Therapy Randomized Trials: A LACE-Bio Pooled Analysis. J. Thorac. Oncol. 2016, 11, 850–861.
  35. Hong, S.; Gao, F.; Fu, S.; Wang, Y.; Fang, W.; Huang, Y.; Zhang, L. Concomitant Genetic Alterations with Response to Treatment and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With EGFR-Mutant Advanced Non-Small Cell Lung Cancer. JAMA Oncol. 2018, 4, 739–742.
  36. Kim, Y.; Lee, B.; Shim, J.H.; Lee, S.H.; Park, W.Y.; Choi, Y.L.; Sun, J.M.; Ahn, J.S.; Ahn, M.J.; Park, K. Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC. J. Thorac. Oncol. 2019, 14, 193–202.
  37. Nahar, R.; Zhai, W.; Zhang, T.; Takano, A.; Khng, A.J.; Lee, Y.Y.; Liu, X.; Lim, C.H.; Koh, T.P.T.; Aung, Z.W.; et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat. Commun. 2018, 9, 216.
  38. Kang, S.; Bader, A.G.; Vogt, P.K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl. Acad. Sci. USA 2005, 102, 802–807.
  39. Kawano, O.; Sasaki, H.; Endo, K.; Suzuki, E.; Haneda, H.; Yukiue, H.; Kobayashi, Y.; Yano, M.; Fujii, Y. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 2006, 54, 209–215.
  40. Yamamoto, H.; Shigematsu, H.; Nomura, M.; Lockwood, W.W.; Sato, M.; Okumura, N.; Soh, J.; Suzuki, M.; Wistuba, I.I.; Fong, K.M.; et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res. 2008, 68, 6913–6921.
  41. Spoerke, J.M.; O’Brien, C.; Huw, L.; Koeppen, H.; Fridlyand, J.; Brachmann, R.K.; Haverty, P.M.; Pandita, A.; Mohan, S.; Sampath, D.; et al. Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin. Cancer Res. 2012, 18, 6771–6783.
  42. Chaft, J.E.; Arcila, M.E.; Paik, P.K.; Lau, C.; Riely, G.J.; Pietanza, M.C.; Zakowski, M.F.; Rusch, V.; Sima, C.S.; Ladanyi, M.; et al. Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol. Cancer Ther. 2012, 11, 485–491.
  43. Scheffler, M.; Bos, M.; Gardizi, M.; König, K.; Michels, S.; Fassunke, J.; Heydt, C.; Künstlinger, H.; Ihle, M.; Ueckeroth, F.; et al. PIK3CA mutations in non-small cell lung cancer (NSCLC): Genetic heterogeneity, prognostic impact and incidence of prior malignancies. Oncotarget 2015, 6, 1315–1326.
  44. Li, S.; Li, L.; Zhu, Y.; Huang, C.; Qin, Y.; Liu, H.; Ren-Heidenreich, L.; Shi, B.; Ren, H.; Chu, X.; et al. Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: A comprehensive mutation profiling from 5125 Chinese cohorts. Br. J. Cancer 2014, 110, 2812–2820.
  45. Ludovini, V.; Bianconi, F.; Pistola, L.; Chiari, R.; Minotti, V.; Colella, R.; Giuffrida, D.; Tofanetti, F.R.; Siggillino, A.; Flacco, A.; et al. Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J. Thorac. Oncol. 2011, 6, 707–715.
  46. Di Cristofano, A.; Pandolfi, P.P. The multiple roles of PTEN in tumor suppression. Cell 2000, 100, 387–390.
  47. Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S.I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R.; et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275, 1943–1947.
  48. Myers, M.P.; Stolarov, J.P.; Eng, C.; Li, J.; Wang, S.I.; Wigler, M.H.; Parsons, R.; Tonks, N.K. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc. Natl. Acad. Sci. USA 1997, 94, 9052–9057.
  49. Balsara, B.R.; Pei, J.; Mitsuuchi, Y.; Page, R.; Klein-Szanto, A.; Wang, H.; Unger, M.; Testa, J.R. Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004, 25, 2053–2059.
  50. Vazquez, F.; Sellers, W.R. The PTEN tumor suppressor protein: An antagonist of phosphoinositide 3-kinase signaling. Biochim. Biophys. Acta 2000, 1470, M21–M35.
  51. Yamamoto, C.; Basaki, Y.; Kawahara, A.; Nakashima, K.; Kage, M.; Izumi, H.; Kohno, K.; Uramoto, H.; Yasumoto, K.; Kuwano, M.; et al. Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib-resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations. Cancer Res. 2010, 70, 8715–8725.
  52. Sos, M.L.; Koker, M.; Weir, B.A.; Heynck, S.; Rabinovsky, R.; Zander, T.; Seeger, J.M.; Weiss, J.; Fischer, F.; Frommolt, P.; et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 2009, 69, 3256–3261.
  53. Wang, F.; Diao, X.Y.; Zhang, X.; Shao, Q.; Feng, Y.F.; An, X.; Wang, H.Y. Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations. Cancer Commun. 2019, 39, 7.
  54. Wu, S.G.; Chang, Y.L.; Hsu, Y.C.; Wu, J.Y.; Yang, C.H.; Yu, C.J.; Tsai, M.F.; Shih, J.Y.; Yang, P.C. Good response to gefitinib in lung adenocarcinoma of complex epidermal growth factor receptor (EGFR) mutations with the classical mutation pattern. Oncologist 2008, 13, 1276–1284.
  55. Tomas, A.; Futter, C.E.; Eden, E.R. EGF receptor trafficking: Consequences for signaling and cancer. Trends Cell Biol. 2014, 24, 26–34.
  56. Vieira, A.V.; Lamaze, C.; Schmid, S.L. Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 1996, 274, 2086–2089.
  57. Goh, L.K.; Huang, F.; Kim, W.; Gygi, S.; Sorkin, A. Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor. J. Cell Biol. 2010, 189, 871–883.
  58. Brankatschk, B.; Wichert, S.P.; Johnson, S.D.; Schaad, O.; Rossner, M.J.; Gruenberg, J. Regulation of the EGF transcriptional response by endocytic sorting. Sci. Signal. 2012, 5, ra21.
  59. Futter, C.E.; Pearse, A.; Hewlett, L.J.; Hopkins, C.R. Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes. J. Cell Biol. 1996, 132, 1011–1023.
  60. Shinde, S.R.; Maddika, S. PTEN modulates EGFR late endocytic trafficking and degradation by dephosphorylating Rab7. Nat. Commun. 2016, 7, 10689.
  61. Oser, M.G.; Niederst, M.J.; Sequist, L.V.; Engelman, J.A. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol. 2015, 16, e165–e172.
  62. Sequist, L.V.; Waltman, B.A.; Dias-Santagata, D.; Digumarthy, S.; Turke, A.B.; Fidias, P.; Bergethon, K.; Shaw, A.T.; Gettinger, S.; Cosper, A.K.; et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 2011, 3, 75ra26.
  63. Youle, R.J.; Strasser, A. The BCL-2 protein family: Opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 2008, 9, 47–59.
  64. Ng, K.P.; Hillmer, A.M.; Chuah, C.T.; Juan, W.C.; Ko, T.K.; Teo, A.S.; Ariyaratne, P.N.; Takahashi, N.; Sawada, K.; Fei, Y.; et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat. Med. 2012, 18, 521–528.
  65. Costa, D.B.; Halmos, B.; Kumar, A.; Schumer, S.T.; Huberman, M.S.; Boggon, T.J.; Tenen, D.G.; Kobayashi, S. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 2007, 4, 1669–1679, discussion 1680.
  66. Cragg, M.S.; Kuroda, J.; Puthalakath, H.; Huang, D.C.; Strasser, A. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med. 2007, 4, 1681–1689, discussion 1690.
  67. Gong, Y.; Somwar, R.; Politi, K.; Balak, M.; Chmielecki, J.; Jiang, X.; Pao, W. Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med. 2007, 4, e294.
  68. Ebi, H.; Oze, I.; Nakagawa, T.; Ito, H.; Hosono, S.; Matsuda, F.; Takahashi, M.; Takeuchi, S.; Sakao, Y.; Hida, T.; et al. Lack of association between the BIM deletion polymorphism and the risk of lung cancer with and without EGFR mutations. J. Thorac. Oncol. 2015, 10, 59–66.
  69. Cho, E.N.; Kim, E.Y.; Jung, J.Y.; Kim, A.; Oh, I.J.; Kim, Y.C.; Chang, Y.S. BCL2-like 11 intron 2 deletion polymorphism is not associated with non-small cell lung cancer risk and prognosis. Lung Cancer 2015, 90, 106–110.
  70. Meador, C.B.; Hata, A.N. Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights. Pharmacol. Ther. 2020, 210, 107522.
  71. Zhang, B.; Zhang, Y.; Zhao, J.; Wang, Z.; Wu, T.; Ou, W.; Wang, J.; Yang, B.; Zhao, Y.; Rao, Z.; et al. M2-polarized macrophages contribute to the decreased sensitivity of EGFR-TKIs treatment in patients with advanced lung adenocarcinoma. Med. Oncol. 2014, 31, 127.
  72. Biswas, A.K.; Han, S.; Tai, Y.; Ma, W.; Coker, C.; Quinn, S.A.; Shakri, A.R.; Zhong, T.J.; Scholze, H.; Lagos, G.G.; et al. Targeting S100A9-ALDH1A1-retinoic acid signaling to suppress brain relapse in EGFR-mutant lung cancer. Cancer Discov. 2022, 12, 1002–1021.
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